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 2018 Revised 28 June 2018 Accepted 11 July 2018
For numbered affiliations see end of article.
Correspondence to Féline P B Kroon;
f. kroon. reum@ lumc. nl
© 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.
AbstrAct
To 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.
InTroduCTIon
In 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.
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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.
MeTHods search strategy
A 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 <20 and premature termination of the trial.
Efficacy outcomes were considered as proposed by the OMERACT core set for domains in clinical trials for hand OA.3 Main efficacy outcomes were pain (preferably measured on visual analogue scale (VAS), numerical rating
scale (NRS), or a validated questionnaire, eg, Austra- lian/Canadian Hand Osteoarthritis Index (AUSCAN) or Michigan Hand Outcomes Questionnaire (MHQ)), hand function (validated questionnaire, eg, Functional Index for Hand OsteoArthritis (FIHOA), AUSCAN or MHQ) and hand strength (grip or pinch strength). Additional efficacy outcomes that were considered included patient global assessment (VAS or NRS), health-related quality of life (Short-Form 36, EuroQoL), structural damage, hand mobility (Hand Mobility in Scleroderma test, modi- fied Kapandji index, fingertip-to-palm-distance) and the number of participants fulfilling the OMERACT-OARSI responder criteria.4 The primary safety outcome was with- drawals due to adverse events (AEs). In addition, serious AEs and AEs broken up by bodily system (eg, gastrointes- tinal, cardiovascular) were assessed. Studies that did not assess any efficacy or safety outcomes were excluded.
study selection, data extraction and risk of bias assessment One reviewer (FK) screened titles and abstracts to deter- mine eligibility for inclusion, according to predefined inclusion criteria, followed by full-text review where neces- sary. In case of doubt, a second reviewer was consulted (MK/LC). Relevant data on study characteristics, inter- ventions, study population and the above-mentioned outcomes was extracted (FK). The risk of bias (RoB) was assessed with regard to random sequence genera- tion, allocation concealment, blinding (participants, care provider, outcome assessor), incomplete outcome data, selective outcome reporting and other sources of bias according to the ‘Cochrane tool’ (FK).5 Each item was judged as low (green colour), high (red) or unclear RoB (yellow; lack of information or uncertainty over potential bias). An ‘overall assessment’ for each study was based on the judgements for each RoB item. Selection bias (sequence generation, allocation concealment) and blinding were considered ‘key domains’, that is, the most important domains in a study’s RoB.
data analysis
Data were only pooled in case of sufficient clinical and statistical homogeneity. For continuous outcomes, data were summarised as mean difference (MD) with corre- sponding 95% CI, unless different measurement instru- ments were used to measure the same outcome, in which case standardised mean differences were calculated. A random effects model was used. Studies that could not be included in the meta-analysis are presented descriptively.
Stata V.14.1 was used for meta-analysis.
resulTs
The literature search yielded 5020 records (after de-du- plication), of which 127 references were included in this review (see figure 1 and online supplementary table S1). Three studies were additionally excluded because of language (Turkish, Chinese). In total, 50 studies assessed benefits and harms of different non-pharma- cological therapies, including one Cochrane review.
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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 interventions
Table 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
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Table 1Characteristics of studies of main non-pharmacological interventions (n=28 studies) RoBStudyDesignInterventionFrequency, duration (instructions)NOA location, definitionWomen (%)Age (years)Primary outcome Exercise Østeras et al 20176SLR (6 RCT, 1 CO)
Hand exercise vs no exercise (N=6); different CMC exercise programme (N=1)6–12 months534Hand (6) or CMC (1), ACR or clinical diagnosisMedian 90Mean 60–81– Joint protection Dziedzic et al 20157Factorial RCTGroup-based joint protection programme (including splints) (JP+, HEx–)4 sessions in 4 weeks62ACR6965.5 (8.6)OARSI-OMERACT responder Group-based exercise programme(HEx+, JP–)656364.5 (9.0) Group-based combination programme: education, joint protection (including splints), exercise (JP+, HEx+)
657166.0 (9.3) Education alone (JP–, HEx–)4 weeks6562 67.2 (9.5) Splints Adams et al 20148 (A) RCTSplint+occupational therapy4 weeks (NR)9CMC, NR7861.2 (9.4)AUSCAN pain Placebo splint+occupational therapy9 Occupational therapy only9 Arazpour et al 20169RCTSplint (custom-made, thermoplast, CMC)4 weeks (use during ADLs, not at night)16CMC, clinical diagnosis and E-L stage I–II8750.2 (5.7)NR No intervention98852.3 (6.4) Bani et al 201316CO (WA+)Splint (custom-made, thermoplast)4 weeks (use during ADLs, not at night)24CMC, clinical diagnosis and E-L stage I-II6753.4NR Splint (prefabricated, neoprene, CMC/MCP)7554.9 No intervention4 weeks117358.6 Becker,et al 201313RCTSplint (custom-made, thermoplast, CMC/MCP)8–10 weeks (use as needed during ADLs and at night)58CMC, clinical diagnosis8062.8 (7.7)DASH Splint (prefabricated, neoprene, CMC)617563.3 (8.5) Cantero-Tellez et al 201614CCTSplint (custom-made, thermoplast, CMC/MCP)12 weeks (use during ADLs (3–4 hours/ day) and at night)44CMC, clinical and Rx diagnosis9359.7 (9.6)NR Splint (custom-made, thermoplast, CMC)409060.5 (9.8) Gomes-Carreira 201010RCTSplint (custom-made, CMC/MCP)12 weeks (NR)20CMC, clinical diagnosis and E-L stage II–III10062.8 (8.5)VAS pain No intervention209065.1 (10.1) Continued on 9 August 2019 at Walaeus Library. Protected by copyright.http://rmdopen.bmj.com/
RoBStudyDesignInterventionFrequency, duration (instructions)NOA location, definitionWomen (%)Age (years)Primary outcome Hermann et al 201311RCTSplint+hand exercises (prefabricated, fabrifoam, CMC/MCP)8 weeks (use as needed)30CMC, ACR, thumb pain9770.7 (7.3)NRS pain Hand exercises2910070.2 (6.2) Rannou et al 200912RCTSplint (custom-made, neoprene, CMC/MCP)1 year (use at night)57CMC, clinical and Rx diagnosis9363.0 (7.9)VAS pain Usual care558563.5 (7.6) Sillem et al 201117CO (WA+)Splint (custom-made, neoprene, CMC/MCP)4 weeks (use when symptomatic, during heavy tasks and at night if preferred)56CMC, clinical diagnosis9164.1 (8.6)AUSCAN function Splint (prefabricated, neoprene, IP to wrist) Wajon et al 200515RCTSplint (custom-made, thermoplast, CMC)+abduction exercise regimen2 weeks splint only, 4 weeks splint +exercise (use full-time)19CMC, clinical diagnosis and E-L stage I–III7459.7 (9.0)NR Splint (custom-made, thermoplast, CMC/ MCP)+pinch exercise regimen218161.2 (12.5) Watt et al 201421CCTSplint (custom-made, thermoplast, DIP)12 weeks (use at night)26DIP, ACR, Rx damage DIP8863 (51–78)NRS pain No intervention26 Weiss et al 200019CO (WA–)Splint (custom-made, thermoplast, CMC)1 week (use when symptomatic)26CMC, clinical and Rx diagnosis8157 (36–88)NR Splint (custom-made, thermoplast, CMC to wrist) Weiss et al 200420CO (WA–)Splint (custom-made, thermoplast, CMC)1 week (use when symptomatic)25CMC, clinical diagnosis and E-L stage I–II84NRNR Splint (prefabricated, neoprene, CMC/MCP) Van der Vegt et al 201718CO (WA+)Splint (custom-made, thermoplast, CMC/MCP)2 weeks (NR)63CMC, clinical and Rx diagnosis7060.1 (8.2)VAS pain Splint (prefabricated, semirigid, CMC) Assistive devices Kjeken et al 201122RCTProvision of assistive devices+information12 weeks (NR)35ACR9761.1 (6.0)COPM Information alone359759.9 (7.5) Combination programme Boustedt 200923RCTGroup-based combination programme: education, joint protection, exercise, splints10 sessions in 5 weeks22CMC, clinical and Rx diagnosis10061 (40–76)NR Group-based joint protection programme2061 (50–76) Dziedzic,et al 20157Factorial RCTGroup-based joint protection programme (including splints) (JP+, HEx–)4 sessions in 4 weeks62ACR6965.5 (8.6)OARSI-OMERACT responder Group-based exercise programme (HEx+, JP–)656364.5 (9.0) Group-based combination programme: education, joint protection (including splints), exercise (JP+, HEx+)
657166.0 (9.3) Education alone (JP–, HEx–)4 weeks656267.2 (9.5) Perez-Marmol et al 201724RCTFine motor skills occupational therapy24 sessions in 8 weeks25Clinical diagnosis8482.8 (8.3)DASH Conventional occupational therapy237479.2 (10) Stamm et al 200225CCTIndividual combination programme: education, joint protection, exerciseSingle session, 3 months20ACR8560.5 (8.3)Grip strength Education alone3 months209060.4 (6.4) Stukstette et al 201326RCTGroup-based combination programme: education, joint protection (including splints), exercise4 sessions in 12 weeks76ACR8260 (7)AUSCAN function, OARSI-OMERACT responder Education alone12 weeks758458 (9)
Table 1Continued Continued on 9 August 2019 at Walaeus Library. Protected by copyright.http://rmdopen.bmj.com/
RoBStudyDesignInterventionFrequency, duration (instructions)NOA location, definitionWomen (%)Age (years)Primary outcome Stukstette et al 201427(A)RCTGroup-based booster session after combination programme26Single session, 1 year147ACR8459 (8)AUSCAN function, OARSI-OMERACT responder No booster session after combination programme261 year Villafane 201328RCTIndividual combination programme: manual therapy, exercise12 sessions in 4 weeks30CMC, clinical diagnosis and Rx damage9082 (2)VAS pain Sham intervention (non-therapeutic ultrasound of the thumb region)308083 (1) Wajon 200515RCTSplint (custom-made, thermoplast, CMC)+abduction exercise regimen2 weeks splint only, 4 weeks splint+excercise; use full-time19CMC, clinical diagnosis and E-L stage I–III7459.7 (9.0)NR Splint (custom-made, thermoplast, CMC/ MCP)+pinch exercise regimen218161.2 (12.5) Values are mean (SD) or median (min–max). Colours denote RoB (green: low, yellow: unclear, red: high). (A) indicates conference abstract. ACR, American College of Rheumatology; ADLs, activities of daily living; AUSCAN, Australian/Canadian Hand Osteoarthritis Index; CMC, first carpometacarpal joint; CO, cross-over trial; COPM, Canadian Occupational Performance Measure; DASH, Disabilities of the Arm, Shoulder and Hand; DIP, distal interphalangeal joint; E-L, Eaton-Litter; FIHOA, Functional Index for Hand OsteoArthritis; IP, interphalangeal joint; MCP,metacarpophalangeal; N, number; NR, not reported; NRS, numerical rating scale; OA, osteoarthritis; RCT, randomised controlled trial; RoB, risk of bias; Rx, radiography; SLR, systematic literature review; VAS, visual analogue scale; WA, wash-out period.
Table 1Continued
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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Table 2Efficacy of main non-pharmacological interventions for hand osteoarthritis from randomised controlled trials/clinical controlled trials InterventionControlOutcomeParticipants (studies), nDurationQuality of evidenceEffect estimate (95%CI)References; comments Exercise Hand exercise No exercise Pain381 (5)12 weeksGRADE: lowSMD −0.27 (−0.47 to −0.07)*6; Cochrane review Function369 (4)12 weeksGRADE: lowSMD −0.28 (−0.58 to 0.02)*Idem OARSI-OMERACT responder305 (3)12 weeksNot reportedRR 2.8 (1.4 to 5.6)*Idem Grip strength362 (5)12 weeksNot reportedSMD 0.34 (−0.01 to 0.69)*Idem Joint protection Joint protection No joint protection Pain257 (1)26 weeksRoB: highMD −0.79 (−1.7 to 0.12) on AUSCAN pain scale (range 0–20)*7; adjusted for age, gender, social class,centre, disease duration Function257 (1)26 weeksRoB: highMD −0.6 (−1.9 to 1.1) on AUSCAN function scale (range 0–36)*Idem OARSI-OMERACT responder257 (1)26 weeksRoB: highOR 2.1 (1.1 to 4.0)*Idem Grip strength257 (1)26 weeksRoB: highMD −0.47 (−1.9 to 0.94) kg†Idem Splints Thumb splint Usual care or no intervention Pain221 (4)4–8 weeksRoB: highMD −2.9 (−12.2 to 6.5) on 100 mm VAS*9–12 Pain137 (2)13–52 weeksRoB: highMD −17.4 (−25.6 to −9.2) on 100 mm VAS*10 12 Function144 (3)4 weeksRoB: highSMD 0.24 (−0.11 to 0.60)†8 9 12; effect estimate based on two trials (n=126)9 12 Function112 (1)52 weeksRoB: highMD −6.3 (−10.9 to −1.7) on Cochin hand function scale (range 0–90)*12 Grip strength95 (2)6–8 weeksRoB: highSMD 0.39 (−0.35 to 1.1)*10 11 Grip strength40 (1)13 weeksRoB: highMD 0.8 (−3.1 to 4.7) kg*10 Long thumb splint (MCP+CMC joint) Short thumb splint (only CMC joint)
Pain185 (3)2–12 weeksRoB: highMD −0.85 (−5.1 to 3.4) on 100 mm VAS*13–15; Wajon: results after splint period used for pooling Function146 (2)9–12 weeksRoB: highMD 1.7 (−0.94 to 4.3)†13 14 DIP splint No intervention Pain26 (1)12 weeksRoB: highMedian difference 0.5 (range −7 to 3.5, p=0.53) on 10 cm VAS*21; outcome: average pain Function26 (1)12 weeksRoB: highNo between-group difference21; no raw data presented Assistive devices Assistive device Information provision Pain70 (1)12 weeksRoB: highMD 0.4 (−9.8 to 10.6) on 100 mm VAS†22; adjusted for baseline Function70 (1)12 weeksRoB: highMD −0.3 (−0.6 to 0.01) on AUSCAN function scale (range 1–5)*22; adjusted for baseline, COPM scores (primary outcome) also significant improvements* Combination programme Continued on 9 August 2019 at Walaeus Library. Protected by copyright.http://rmdopen.bmj.com/
InterventionControlOutcomeParticipants (studies), nDurationQuality of evidenceEffect estimate (95%CI)References; comments Combination programme: education, joint protection, exercise
Education alone Pain321 (3)12 weeksRoB: highMD 0.40 (−0.50 to 1.3) on AUSCAN pain scale (range 0–20)†7 25 26; effect estimate based on one trial (n=151),26adjusted for baseline Function321 (3)12 weeksRoB: highMD 0.49 (−1.0 to 2.0) on AUSCAN function scale (range 0–36)*7 25 26; effect estimate based on one trial (n=151),26adjusted for baseline OARSI-OMERACT responder281 (2)12 weeksRoB: highOR 0.82 (0.42 to 1.6)†7 26; effect estimate based on one trial (n=151)26 Grip strength321 (3)12 weeksRoB: highSMD −0.21 (−0.49 to 0.08)†7 25 26; effect estimate based on two trials (n=186)25 26 Quality of evidence:GRADE: very low/low RoB: high
GRADE: moderate RoB: unclearGRADE: high RoB: lowEffect estimate:No effectBetween-group difference *In favour of the intervention group. †In favour of the control group. AUSCAN, Australian/Canadian Hand Osteoarthritis Index; CMC, first carpometacarpal; COPM, Canadian Occupational Performance Measure; DIP, distal interphalangeal joint; idem, same as above; MCP, metacarpophalangeal joint; MD, mean difference; OA, osteoarthritis; RoB, risk of bias; RR, risk ratio; SMD, standardised mean difference; VAS, visual analogue scale.
Table 2Continued
Pharmacological interventions
Table 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 interventions
Topical 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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Table 3Characteristics of studies of main pharmacological interventions (n=33 studies) RoBStudyDesignInterventionFrequency, durationNOA location, definitionWomen (%)Age (years)Primary outcome Topical NSAIDs Altman et al 200952RCTTopical diclofenac gel 1%4 per day, 8 weeks198ACR, Rx KL1–37763.6 (10.3)VAS pain, AUSCAN, VAS patient global Topical placebo cream1877764.7 (9.6) Graber et al 199739RCTTopical ibuprofen cream3 per day, 2 weeks57ACR or clinical diagnosis isolated CMC OA9165.8 (8.6)FIHOA Berthollet treatment (local steam bath and finger shower)Daily, 3 weeks598663.2 (10.0) Michalsen et al 200892RCTDiclofenac gel 10 mg/g2 per day, 4 weeks16CMC, clinical diagnosis and Rx damage10064.3 (9.1)VAS pain Medicinal leechesOnce in 4 weeks1664.1 (6.4) Romero et al 201355RCTTopical diclofenac gel 2%3 per day, 4 weeks65ACR8662 (10.2)NR Topical herbal cream6595 Talke et al 198550RCTTopical etofenamate 100 mg/g3 per day, 3 weeks30IP, clinical diagnosis, 'activated'8364.3 (13.5)NR Oral indomethacin 150 mg/day3 weeks309063.3 (11.0) Widrig et al 200754RCTTopical ibuprofen cream 5%3 per day, 3 weeks99ACR6164 (11.4)VAS pain, FIHOA Topical arnica cream 50%1056764 (12.0) Zacher et al 200151RCTTopical diclofenac gel 1%4 per day, 3 weeks165IP, clinical diagnosis, 'activated'8660.7 (9.4)VAS pain improve≥40% Oral ibuprofen 1200 mg/day3 weeks1569063.2 (9.4) Oral NSAIDs Dreiser et al 199362RCTIbuprofen 800 mg/day2 weeks30Rx damage, pain exacerbation8058.5 (1.7)NR Placebo309060.3 (2.0) Grifka et al 200463RCTLumiracoxib 200 mg/day4 weeks205ACR8262.0 (12.1)VAS pain Lumiracoxib 400 mg/day1938361.0 (12.4) Placebo1968362.7 (11.7) Muratore et al 200465 (A)RCTKetoprofen lysine salt 160 mg/ day+glucosamine+chondroitin sulfate20 days30Hand, NR100NRNR Glucosamine+chondroitin sulfate28 Rovetta et al,2001-B49CCTDexketoprofen-trometamol 50 mg/day3 weeks35ACR, 'active OA'8657.7 (3.4)Morning stiffness (WOMAC) No intervention1963 Rovetta et al, 2001-A48CO (WA-)Dexketoprofen-trometamol 50 mg/day13 days36ACR, 'active OA'NRNRMorning stiffness and pain (WOMAC) Paracetamol 1000 mg/day Seiler 198364RCTMeclofenamate sodium 300 mg/day4 weeks22Clinical diagnosis,≥1 inflamed DIP and Rx damage9562.5 (34–77)NR Placebo198465.0 (49–80) Talke 198550RCTOral indomethacin 150 mg/day3 weeks30IP, clinical diagnosis, 'activated'8364.3 (13.5)NR Topical etofenamate 100 mg/g3 per day, 3 weeks309063.3 (11.0) Zacher et al 200151RCTOral ibuprofen 1200 mg/day3 weeks156IP, clinical diagnosis,'activated'9063.2 (9.4)VAS pain improve≥40% Topical diclofenac gel 1%4 per day, 3 weeks1658660.7 (9.4) Chondroitin sulfate Continued on 9 August 2019 at Walaeus Library. Protected by copyright.http://rmdopen.bmj.com/
RoBStudyDesignInterventionFrequency, durationNOA location, definitionWomen (%)Age (years)Primary outcome Gabay et al 201166RCTChondroitin sulfate 800 mg/day6 months80ACR7363.9 (8.5)VAS pain, FIHOA Placebo827663.0 (7.2) Verbruggen 200244RCTChondroitin polysulphate 50 mg/day intramuscularly3 years66IP, clinical diagnosis and Rx damage9155.2 (6.7)Rx progression Placebo intramuscularly649756.1 (9.2) RCTChondroitin sulfate 1200 mg/day3 years44IP, clinical diagnosis and Rx damage9157.6 (7.1)Rx progression Placebo488855.9 (8.9) Intra-articular glucocorticoids Bahadiret al 200973RCTGlucocorticoid i.a. 20 mg/0.5 mLOnce20CMC, Rx E-L stage II–III10062.9 (9.1)NR Hyaluronic acid i.a. 5 mg/0.5 mL1 per week, 3 weeks2060.8 (7.3) Fuchs et al 200674RCTGlucocorticoid i.a. 10 mg/1 mL1 per week, 3 weeks28CMC, clinical diagnosis and Rx KL>080Median 61.0NR Hyaluronic acid i.a. 10 mg/1 mL28Median 59.5 Heyworth et al 200868RCTGlucocorticoids i.a.1 mLOnce+1 i.a. placebo, 2 weeks22CMC, Rx E-L stage I–IV9060 (9.4)NR Hyaluronic acid i.a. 8 mg/1 mL1 per week, 2 weeks288065 (10.6) Placebo i.a. (1 mL, saline)1 per week, 2 weeks188964 (8.5) Jahangiri 201493RCTGluocorticoid i.a. 40 mg/0.5 mL+0.5 mL lidocaineOnce+2 i.a. placebo, 3 weeks30CMC, clinical diagnosis and Rx E-L stage>I7063.3 (10.1)VAS pain Dextrose i.a. 100 mg/0.5 mL+0.5 mL lidocaine1 per week, 3 weeks307763.9 (9.4) Mandl,et al 201269(A)RCTGlucocorticoid i.a. 40 mg/1 mLOnce+1 i.a. placebo,2 weeks65CMC, clinical diagnosis and Rx KL>06866.5 (45–89)NR Hyaluronic acid i.a. 8 mg/1 mL1 per week, 2 weeks62 Placebo i.a. (1 mL, bupivacaine)1 per week, 2 weeks61 Meenagh et al 200470RCTGlucocorticoid i.a. 5 mg/0.25 mLOnce20CMC, NR9560.6 (41–71)VAS pain improve≥20% Placebo i.a. (0.25 mL, saline)208559.3 (46–69) Monfort et al 201475RCTGlucocorticoid i.a. 3 mg/0.5 mL1 per week, 3 weeks40CMC, clinical diagnosis and Rx KL1–38862.8 (8.7)FIHOA Hyaluronic acid i.a. 5 mg/0.5 mL48 Spolidoro,et al 201571RCTGlucocorticoid i.a.4 mg/0.2 mL (DIP) or 6 mg/0.3 mL(PIP)+0.1 mL lidocaineOnce30IP, clinical diagnosis and Rx osteophyte10060.7 (9.1)VAS pain, VAS joint swelling Placebo i.a. (0.1 mL, lidocaine)309360.7 (7.3) Stahl et al 200576RCTGlucocorticoid i.a. 40 mg/1 mLOnce25CMC, Rx E-L stage II8462 (50–91)NR Hyaluronic acid i.a. 15 mg/1 mL2792.562 (37–80) Oral glucocorticoids Kvien et al 200881RCTPrednisone 3 mg/day+dipyridamole 200 mg/ day6 weeks42ACR, Rx KL>19361.1 (5.0)AUSCAN pain Placebo419359.6 (5.3) Wenham et al 201282RCTPrednisone 5 mg/day4 weeks35ACR, Rx KL>07461.9 (6.6)VAS pain Placebo358961.1 (9.0)
Table 3Continued Continued on 9 August 2019 at Walaeus Library. Protected by copyright.http://rmdopen.bmj.com/
RoBStudyDesignInterventionFrequency, durationNOA location, definitionWomen (%)Age (years)Primary outcome Hydroxychloroquine Basoski et al 201583(A)RCTHydroxychloroquine 400 mg/day24 weeks98ACR8657VAS pain Placebo98 Kingsbury,et al 201684(A)RCTHydroxychloroquine 200–400 mg/day1 year124ACRNRNRNRS pain Placebo124 McKendry et al 200159(A)RCTHydroxychloroquine 400 mg/day24 weeks29Hand, NRNRNRNR Paracetamol 3900 mg/day29 Placebo30 TNF inhibitors Aitken et al 201746(A)CO (WA+)Adalimumab 40 mg subcutaneously2 subcutaneously per 2 weeks,12 weeks43ACR, erosive (Rx erosion), MRI synovitis7761 (8.4)AUSCAN pain Placebo subcutaneously Chevalier et al 201585RCTAdalimumab 40 mg subcutaneouslyOnce 2 subcutaneously,2 weeks 42ACR, Rx damage IPs8762.8 (6.9)VAS pain improve≥50% Placebo subcutaneously438362.2 (7.0) Kloppenburg et al 201647 86 87 (A)
RCTEtanercept 25–50 mg subcutaneously1 subcutaneously per week, 1 year45IP, ACR, erosive (Rx erosion IP)8259.4 (6.5)VAS pain Placebo subcutaneously458060.1 (8.7) Verbruggen et al 201245RCTAdalimumab 40 mg subcutaneously1 subcutaneously per 2 weeks, 1 year
30IP, ACR, erosive (Rx erosion IP)8761.9 (6.1)Rx progression Placebo subcutaneously308360.7 (6.9) Values are mean (SD) or median (min-max). Colours denote RoB (green:low, yellow: unclear, red: high). (A) indicates conference abstract. ACR,American College of Rheumatology; AUSCAN, Australian/Canadian Hand Osteoarthritis Index; CCT, clinical controlled trials; CMC, first carpometacarpal; CO, cross-over trial; FIHOA, Functional Index for Hand OsteoArthritis; i.a., intra- articular; IP, interphalangeal joint; NR, not reported; NRS, numerical rating scale; NSAID, non-steroidal anti-inflammatory drugs; OA, osteoarthritis; RCT, randomised controlled trial; TNF, tumour necrosis factor; VAS, visual analogue scale; WA, wash-out period; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index.
Table 3Continued on 9 August 2019 at Walaeus Library. Protected by copyright.http://rmdopen.bmj.com/
Table 4Efficacy of main pharmacological interventions for hand osteoarthritis from randomised controlled trials/clinical controlled trials InterventionControlOutcomeParticipants (studies), nDuration
Specific OA location or typeQuality of evidenceEffect estimate (95%CI)References; comments Topical NSAIDs Topical NSAID Topical placebo Pain385 (1)8 weeks–RoB: lowMD −5.9 (−11.7 to −0.06) on 100 mm VAS*52 Function385 (1)8 weeks–RoB: lowMD −7.3 (−12.9 to −1.7) on AUSCAN function scale (range 0–36)*
52 OARSI- OMERACT response
385 (1)8 weeks–RoB: lowRR 1.2 (0.99 to 1.4)*52 Topical NSAID Oral NSAID Pain381 (2)3 weeks'Activated' IP OARoB: lowSMD −0.05 (−0.27 to 0.17)*50 51; effect estimate based on one trial (n=321)51; same studies as previous SLR1 Grip strength381 (2)3 weeks'Activated' IP OARoB: lowMD −0.01 (−0.03 to 0.01) bar*50 51; effect estimate based on one trial (n=321)51 Oral NSAIDs Oral NSAID Placebo Pain695 (3)2–4 weeks–RoB: lowSMD 0.40 (0.20 to 0.60)*62–64; effect estimate based on two trials with ibuprofen 800 mg and lumiracoxib 200–400 mg (n=654)62 63; same studies as previous SLR1 Function695 (3)2–4 weeks–RoB: lowSMD 0.17 (−0.03 to 0.36)*Idem Chondroitin sulfate Chondroitin sulfate Placebo Pain162 (1)26 weeks–RoB: lowMD −8.7 (p=0.016) on 100 mm VAS*66 Function162 (1)26 weeks–RoB: lowMD −2.1 (p=0.008) on FIHOA (range 0–30)*66 Grip strength162 (1)26 weeks–RoB: lowMD 1.9 (−0.02 to 3.8) kg*66 Intra-articular therapies Intra-articular glucocorticoids Intra-articular placebo Pain206 (3)26 weeksCMCRoB: low (1), unclear (1)
MD −3.6 (−13.9 to 6.8) on 100 mm VAS*68–70; effect estimate based on two trials (n=166)69 70 Function166 (2)26 weeksCMCRoB: unclearMD −1.5 (−6.3 to 3.3) on DASH (range 0–100)*68 69; effect estimate based on one trial (n=126)69 Continued on 9 August 2019 at Walaeus Library. Protected by copyright.http://rmdopen.bmj.com/
