Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: A randomised, multicentre, double-blind, placebo-controlled trial

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Adalimumab in patients with hand osteoarthritisrefractory to analgesics and NSAIDs: a randomised,multicentre, double-blind, placebo-controlled trialX Chevalier,1 P Ravaud,2 E Maheu,3 G Baron,2 A Rialland,4 P Vergnaud,5 C Roux,6

Y Maugars,7 D Mulleman,8 C Lukas,9 D Wendling,10 P Lafforgue,11 D Loeuille,12

V Foltz,13 P Richette,14 On behalf of the French section of osteoarthritis

Handling editor Tore K Kvien

▸ Additional material ispublished online only. To viewplease visit the journal online(http://dx.doi.org/10.1136/annrheumdis-2014-205348).

For numbered affiliations seeend of article.

Correspondence toProfessor Xavier Chevalier,Department of Rheumatology,Henri Mondor Hospital,Creteil 94010, France;[email protected]

Received 4 February 2014Revised 31 March 2014Accepted 13 April 2014

To cite: Chevalier X,Ravaud P, Maheu E, et al.Ann Rheum Dis PublishedOnline First: [please includeDay Month Year]doi:10.1136/annrheumdis-2014-205348

ABSTRACTAim To test the efficiency of tumour necrosis factorblockers (adalimumab) in patients with painful refractory(non-responders to analgesics and non-steroidalanti-inflammatory drugs (NSAIDs)) hand osteoarthritis (OA).Methods We performed a randomised, double-blind,placebo-controlled, parallel group, multicentre study.Patients were randomised to: 1/1 adalimumab 40 mg fortwo subcutaneous injections at a 15-day interval or placeboand monitored for 6 months. The primary outcome was thepercentage of patients with an improvement of more than50% in global pain (Visual Analogue Scale) between week0 (W0) and week 6 (W6). Secondary outcomes included thenumber of painful joints, swollen joints, morning stiffnessduration, patient and practitioner global assessments,functional indexes for hand OA, and consumption ofanalgesics. Analysis on the mean primary outcome measurewas done on patients who received at least one injection.Results 99 patients were recruited and 85 patients wererandomised. Among them, 37 patients in the placebo groupand 41 in the adalimumab group received at least oneinjection and were evaluated at W6 (n=78) on the mainefficacy outcome. Mean age was 62 years, 85% werewomen, and mean level of pain was 62 mm at W0. At W6,35.1% in the adalimumab group versus 27.3% in theplacebo group had a pain reduction ≥50% (RR 1.12 (95%CI 0.82 to 1.54; p=0.48). There were no statisticaldifferences for all secondary end points. The rate of adverseevents was similar in the two groups.Conclusions Adalimumab was not superior to placebo toalleviate pain in patients with hand OA not responding toanalgesics and NSAIDs.Trials registration number NCT00597623.

INTRODUCTIONDigital hand osteoarthritis (OA) involving the prox-imal and distal interphalangeal (IP) joints is the mostfrequent form of OA, affecting middle-aged womenand the elderly (reaching a radiological prevalence of80%).1 2 Symptomatic hand OA in subjects aged morethan 70 years affects 13% of men and 26% ofwomen.3 Among symptomatic patients, there is asubset of difficult-to-treat patients, frequently women,who present a high level of pain and disability despitean optimal combination of non-pharmacological andpharmacological treatments, as recommended.4–6 Thisclinical setting may be associated with the presence onX-rays of central subchondral erosions in IP joints andis named erosive hand OA.4

In this setting, several disease-modifying drugsused in inflammatory arthritis such as methotrex-ate, sulfasalazine and hydroxychloroquine havebeen tried, but without any proven efficacy.7 8

Therefore, there is a real need for an emergingeffective therapy in hand OA where the impact onthe patient’s daily quality of life could be as severeas in rheumatoid arthritis.9 10 Patients sufferingfrom such a severe form of hand OA may developfurther the feeling of a neglected disease.11 12

Tumour necrosis factor (TNF) α is a well-knownpro-inflammatory cytokine produced by the synovialcells and chondrocytes in OA which, together withinterleukin (IL)-1 b, plays a pivotal role in cartilagematrix degradation.13–18 Beyond its pro-inflammatoryeffects, TNF a further activates sensory neuronsthrough PGE2 release, and increases the expression ofthe neurotrophin nerve growth factor, which is a keymediator of pain in OA, present in synovial fluid andinflamed synovial membrane.19 20

In addition, because patients with severe handOA may present signs of inflammation in the IPjoints that can mimic peripheral psoriatic arthritis(PsA), with synovitis seen in ultra-sonography or byMRI, it has been hypothesised that TNF α mayplay an important role in this disease.21–23

In vitro, blocking TNF action decreases produc-tion of enzymes and pro-inflammatory mediators inOA cartilage explants.24 Targeting synovial mem-brane inflammation by TNF α blockers has showndramatic effect on symptoms and structure inpatients with PsA and rheumatoid arthritis.25 Bycontrast, there are very little data on the effect ofanti-TNFα in patients with hand OA and no wellconducted randomised controlled trials (RCTs)focused on evolution of symptoms.26–28

The objective of this study was to test thehypothesis that TNF α blockers have a symptomaticefficacy in patients suffering from hand OA with ahigh level of pain and no response to analgesic andnon-steroidal anti-inflammatory drugs (NSAIDs), inorder to face a pragmatic situation where the prac-titioners miss any efficient therapeutic issues.

METHODSTrial designThis is a randomised, double-blind, parallel group,placebo-controlled, 6-month, multicentre trial (16active sites among 20) testing the efficacy of a TNF

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α blocker adalimumab (two subcutaneous injections of 40 mgeach at a 2-week interval) in patients with hand OA who do notrespond to analgesics and NSAIDs (the so-called refractory handOA), according to international guidelines. The protocol andamendments were approved by the Independent EthicsCommittees from Henri Mondor Hospital (Creteil, France). Asrequired by legislation, the research was authorised by theFrench Regulatory Agency. The study was conducted in accord-ance with the International Conference on HarmonizationGuideline for Good Clinical Practice and the Declaration ofHelsinki. This trial has been registered at ClinicalTrials.gov (n°NCT00597623).

This is an academic study sponsored by the AssistancePublique-Hopitaux de Paris.

Eligibility of patientsEligible patients were adults with painful hand OA meeting theclassification criteria of the American College of Rheumatologyfor hand OA and not responding to analgesics and NSAIDs.29

Inclusion criteria included: aged between 40 and 80, at leastthree IP joints symptomatic for more than 3 months, a level ofpain over 40 mm (global pain in the last 24 h), non-respondingto analgesics level 1 or 2, and to NSAIDs for at least 10 days inthe past 3 months. X-rays of the hand should have shown atleast three IP joints with OA features (Kellgren and Lawrencesuperior or equal to grade 2). Women of child-bearing ageshould use an effective contraceptive method. Patients wererecruited by referral and gave their informed consent to partici-pate after receiving comprehensive information.

Exclusion criteriaThey included women of child-bearing age who are not usingcontraception; previous therapies by TNF α blockers; secondaryhand OA (to previous inflammatory diseases) and any painfulsyndrome of the upper limb which may interfere with evalu-ation of hand pain; inflammatory diseases and contraindicationsto anti-TNF α therapies such as acute or chronic infectiousstates, latent tuberculosis meaning either history of a primoinfection (positive tuberculin test=10 mm following 5UI asstated by the French security agency) or risk of reactivation ofsilent tuberculosis (previous history of untreated tuberculosis,recent contact with a person suspected of having active tubercu-losis, phlyctenular or positive tuberculin test, pulmonary sequelof tuberculosis); infection with HIV or hepatitis viruses(C and B); conditions with increased risk factors for infectiousdisease such as chronic cutaneous ulcers, urinary catheters andprevious infection from any medical devices; cancers or malig-nant blood diseases except previous cancer history if cured forat least 5 years, baso cellular cutaneous cancer; any precancer-ous conditions (intestinal polyps, cervical dysplasia, the start ofmonoclonal gammapathy proliferation, myelodysplasia syn-dromes); demyelinating disease of the central nervous system,severe cardiac insufficiency and high level of antinuclear anti-bodies (<1/800); leucopenia; kidney insufficiency (creatineclearance <50 mL: min); hepatic cytolysis; skin disease whichcontraindicated subcutaneous injections and cutaneous psoriasis;anticoagulant therapies, scheduled surgery for hand OA or anysurgical procedure anticipated within the next 6 months;intra-articular injections of corticosteroids in the past month orhyaluronic acid (HA) intra-articular injection in IP joints in the3 months prior to joining the study; slow-acting drugs for OA(soybean and avocado extracts, glucosamine, chondroitin, dia-rcerhein) started less than 6 months prior to the study; othertreatments for hand OA such as methotrexate,

hydroxychloroquine and salazopyrine; colchicine; oral corticos-teroids; psychiatric disorders; unstable diabetes; patients whoare not registered with social security; and history of alcoholabuse.

Study settingThe study was conducted in 16 rheumatological departmentsfrom tertiary care hospitals centres in France.

InterventionsDuring the preinclusion period, after screening and before thefirst injection in the following 7–28 days, eligibility criteria werechecked. At day 0 (named W0), the patient received the firstinjection. The second injection was performed 15 days later(named W2) and the following assessment visits were done atweeks 6, 10, 14 and 26. At the W0 visit, each patient under-went a physical examination and vital signs were recorded.At each visit, items representing secondary efficacy end pointswere recorded (listed in the Clinical variables section).

Prohibited/authorised treatmentsFor all visits, analgesics and NSAIDs should be stopped 72 hbefore. Authorised treatments included only acetaminophen(up to 4 g/day). NSAIDs were not authorised until W6 (corre-sponding to 4 weeks after the second injection).

SafetySafety was evaluated at each visit and the patient was advised toinform the medical staff of any emerging medical problems (fordefinition of adverse events see online supplementary file).

Blood and urine samples were collected at W0 and at W6 forbiomarker studies (see online supplementary file, includingdosage in the serum of cartilage oligomeric matrix protein(COMP), HA, high-sensitivity C reactive protein (hsCRP),PIIANP (type IIA collagen N-propeptide), IL-1 β, IL-6 and TNFα, and in the urine, level of CTX II (degradation products ofC-terminal telopeptides of type II collagen).

Outcome measures and follow-upClinical variablesOur primary efficacy end point was the percentage of patientsachieving a pain improvement of at least 50% on a 0–100 mmVisual Analogue Scale (VAS) between W0 and W6. The questionasked was: ‘What is the global level of pain in your hands in thepast 24 h?’

Secondary efficacy outcomes were mean change in pain levelassessed on a 0–100 mm VAS between W0 and W6 andbetween W0 and W26. Other secondary efficacy parameterswere evaluated at W6 and W26: pain (on a 0–100 mm VAS),duration of morning stiffness (minutes), patient global assess-ment on a 0–100 mm VAS, practitioner global assessment on a0–100 mm VAS, number of painful IP joints (0–30), number ofpainful IP joints under digital pressure (0–30), number ofswollen IP joints (0–30), evolution of FIHOA (0–30), evolutionof Cochin Hand Functional index (0–90), and consumption ofanalgesics between the two groups.30 31 Data for all efficacyparameters were collected at weeks 2, 4, 6, 10, 14 and 26.

Concerning rescue medications, patients were classified asnon-users, or occasional and daily users, and their consumptionwas analysed.

Biological variablesCytokines and biochemical markers of joint metabolism weremeasured with commercially available kits, using assay

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procedures specified by the manufacturers (see online supple-mentary file). Serum samples and fasting second morning voidurine were collected before injection, at W0 and at W6.

Sample size calculationWe hypothesised a 60% rate of responders at 6 weeks (painimprovement of at least 50%) in the adalimumab group and30% in the placebo group, with an a risk of 5% and a power of80%. The sample size had to be 42 patients per group.Anticipating 20% of patients prematurely withdrawing from thetrial, 110 patients (55 per group) had to be included.

RandomisationParticipants were randomised with a 1:1 ratio to adalimumab(Abbott) at 40 mg for two subcutaneous injections, at a 15-dayinterval, or placebo using a computer-generated central random-isation schedule.

The list of randomisation was created by Abbott, usingClinicocopia statistical software, using a random block size ofeight and independently of investigators involved in the trial.After the investigator had obtained the patient’s informedconsent and had verified the inclusion/exclusion criteria, a faxwas sent to the URC Mondor which subsequently assigned theallocated treatment. An independent pharmacist dispensed theallocated treatment.

The randomisation was centralised and not stratified.Each syringe was masked with an identical volume of 0.8 mL,

conditioned in a block of two syringes, stored at 2–4°C. Theywere prepackaged and consecutively numbered for each patientaccording to the randomisation schedule. Each patient wasassigned an order number.

BlindingPatients and physicians were blinded to treatments. Each sub-cutaneous injection was performed by a nurse, independently ofthe medical investigators and of the outcome measures. Allinvestigators, staff and participants were kept unaware of theoutcome measurements and trial results.

Statistical analysisAll statistical analyses were performed at an independent centre(Hotel-Dieu Hospital, Paris, France), using SAS software, V.9.3(SAS Institute Inc). A two-sided p<0.05 was retained for eachanalysis. Means and SDs or median with first and third quartileswere used to summarise distributions and means with a 95% CIwere used to summarise group differences. Efficacy analyseswere conducted on all randomised patients having received atleast one injection. A post hoc analysis on the primary outcomewas performed on the subpopulation with at least three swollenjoints at baseline. Selection of patients and follow-up have beendescribed according to the consort statement.32

The percentage of patients with more than a 50% of improve-ment in pain VAS in each group was compared using a log-binomial regression (with a log link and a binomial distribution).Clustering due to centre was taken into account using general-ised estimating equations with an independence or exchangeableworking correlation structure. A relative risk with a 95% CI wascomputed. To impute missing data, we assumed that all missingparticipants did not experience the 50% improvement. As a sen-sitivity analysis, we assumed that all participants experiencedthe 50% improvement.

For quantitative secondary outcomes, we used the mixedeffects model for repeated measurements to estimate andcompare adjusted mean changes from baseline to 6 weeks and

from baseline to 26 weeks. The likelihood-based model uses allavailable data and provides valid results under the assumptionthat missing data are missing at random. Fixed effects includedthe baseline value of the outcome, centre, treatment, time andtreatment by time interaction. An unstructured correlationmatrix was used to model the within-subject error correlationstructure. Changes between groups at W6 in joint biomarkers,hsCRP and cytokine levels were compared according to aMann–Whitney test. Correlations between change in TNF levelsand changes in clinical outcomes at W6 in patients treated withadalimumab were assessed by a Spearman correlationcoefficient.

RESULTSFlow chartFigure 1 shows the study flow chart of participants. Of the 99recruited patients from 16 centres who gave their informedconsent after receiving extensive information about the trial,14 were excluded before randomisation. A total of 85 patientswere enrolled and randomly assigned (42 in the adalimumabgroup and 43 in the placebo group). Of these, two patients (onein each group) were further excluded from all statistical analysesbecause it was impossible to determine which treatment wasfinally received after allocation (mistake in treatment allocationdue to a computer glitch). In the placebo group, five patientswho did not receive the allocated intervention (two excludedfor impossibility of a normal follow-up, one for refusinginformed consent, one for contraindication for TNF therapyand one for a misunderstanding), while blinding was main-tained, were also excluded for comparative analyses. Moreover,these five patients have baseline data for demographic character-istics but not for efficacy outcomes (baseline or follow-up).Finally, 41 in the adalimumab group received at least one injec-tion and 37 patients in the placebo group made up the popula-tion for the main efficacy analysis.

RecruitmentThe recruitment period began in January 2008 and ended inOctober 2009. Participants attended clinical visits at weeks 0, 2,4, 6 (main outcome), 10, 14 and 26.

Patient characteristicsThe adalimumab and the placebo groups had similar character-istics, except the baseline level of pain which was slightly higherin the adalimumab group: 67.1±13.1 versus 63.6±12.7 mm inthe placebo group (table 1). For the whole population, the meanage of patients (85.8% women) was 62.5±6.9 years with amean Body Mass Index of 24.9±4.07 kg/m2. Mean disease dur-ation of symptomatic hand OA was identical in both groups:13.5 years. The majority of patients were taking an ongoingtreatment for their hand OA (83%). The most painful hand OAwas the right hand in 54% of cases.

Primary outcome efficacy analysisIn the mITT set (defined as patients who received at least oneinjection), the primary outcome at W6 was missing in 4/37patients in the placebo group and in 4/41 patients in the adali-mumab group (table 2). With respect to the percentage ofpatients with pain improvement of more than 50% at W6, therewas no difference between the groups: 35.1% of adalimumab-treated patients were responders compared with 27.3% ofplacebo-treated patients (RR=1.12; 95% CI 0.82 to 1.55;p=0.47). Considering missing values as non-responders in bothgroups and taking into account the centre effect, the relative

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risk was RR=1.10 (95% CI 0.82 to 1.49; p=0.51). Consideringmissing values as responders, results were the same: RR 1.11,95% CI (0.82 to 1.52), p=0.50.

Secondary outcome measuresResults are reported for all secondary outcome measures intable 3. The difference in the mean change in pain score on theVAS (0–100 mm) over 6 weeks between adalimumab andplacebo was: −2.5 mm (95% CI −14.0 to 9.0), p=0.67(table 2).33 Similarly, the mean difference in pain score on VAS(0–100 mm) at W26 was not different between the groups:−1.4 (95% CI −13.0 to 10.1; p=0.80). The course of thechanges in pain score in the two groups is given in figure 2.

There was no difference in any secondary end points betweenthe two groups either at W6 or W26, except for the decrease inthe number of swollen joints between W0 and W26 whichfavoured the adalimumab group: mean between-group differ-ence: −1.9 (95% CI −3.2 to −0.6; p=0.006). The percentageof patients with analgesic intake did not differ between the two

groups (70% in the placebo group and 68% in the adalimumabgroup; p=0.85).

A post hoc analysis on the evolution of pain in patients withat least three swollen joints at baseline was performed andfound no difference between the two groups in this subset(n=30 in the adalimumab group and n=27 in the placebogroup). After considering missing values as non-responders inboth groups and taking into account the centre effect, RR was1.08 (95% CI 0.84 to 1.38; p=0.56).

Analysis of biomarkersBaseline levels of the different biomarkers in the two groups aresummarised in table 1. Changes at W6 in joint biomarkers, CRPlevels and cytokine levels after treatment with placebo or adali-mumab are summarised in table 4. There was no difference inthe changes for any biomarkers between the two groups. Finally,we assessed whether changes in the TNF a level were linked tothe clinical outcome at W6 in the group of patients treated with

Figure 1 Flow chart of the study.

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Table 1 Baseline characteristics of patients with hand OA

Baseline characteristics N Adalimumab N Placebo

Age, years (mean (SD)) 41 62.8 (6.9) 42 62.2 (7.0)Women, n (%) 41 36 (87.8%) 42 35 (83.3%)Weight, kg (mean (SD)) 41 66.2 (13.0) 42 66.8 (13.9)Height, cm (mean (SD)) 41 162.2 (7.3) 42 164.0 (8.5)Body Mass Index, kg/m2 (mean (SD)) 41 25.2 (4.6) 42 24.7 (3.5)Duration of disease (years) (mean (SD)) 41 13.5 (9.8) 42 13.5 (9.1)Dominant side affected, n (%)Right 41 22 (53.7%) 42 23 (54.8%)Left 10 (24.3%) 42 8 (19.0%)Idem 9 (22.0%) 42 11 (26.2%)

Manual activities >4 h, n (%) 41 13 (33.3%) 42 15 (35.7%)Familial history of hand OA, n (%) 41 15 (36.6%) 42 10 (23.8%)Pain score (VAS, 0–100 mm) (mean (SD)) 40 67.1 (13.1) 37 63.6 (12.7)Morning stiffness (min) (mean (SD)) 40 42.7 (59.3) 37 34.9 (40.1)No of painful joints (spontaneous; 0–30) (mean (SD)) 41 10.7 (6.2) 37 9.5 (6.3)No of painful joints (pressure; 0–30) (mean (SD)) 41 13.0 (5.6) 37 13.4 (6.3)No of swollen joints (0–30) (mean (SD)) 41 6.4 (4.6) 37 5.7 (4.2)Dreiser Index (range 0–30) (mean (SD)) 41 15.9 (6.8) 37 15.5 (6.0)CHFS (range 0–90) (mean (SD)) 41 37.4 (22.1) 37 35.6 (18.5)Physician global assessment (VAS, 0–100 mm) (mean (SD)) 39 63.2 (12.9) 36 58.9 (12.0)Patient global assessment (VAS, 0–100 mm) (mean (SD)) 40 67.0 (18.0) 37 59.9 (16.4)Kellgren and Lawrence score (0–128) (median (Q1, Q3) 39 49.0 (39.0; 59.0) 35 51.0 (35.0; 61.0)Verbruggen score (0–218) (median (Q1, Q3) 39 39.9 (28.4; 60.9) 35 32.7 (20.7; 61.6)SYSADOA, n (%) 41 15 (36.6%) 42 23 (54.8%)Current treatments, n (%) 41 33 (80.5%) 42 36 (85.7%)

Acetaminophen, n (%) 41 23 (56.1%) 42 22 (52.4%)NSAIDs, n (%) 41 14 (34.1%) 42 20 (47.6%)Analgesics level 2, n (%) 41 9 (22.0%) 42 11 (26.2%)Orthesis, n (%) 41 4 (9.8%) 42 6 (14.3%)PIIANP, ng/mL (median (Q1, Q3)) 39 645.8 (558.4; 761.5) 32 604.3 (517.3; 796.3)uCTX-II/Creat (median (Q1, Q3)) 39 345.6 (194.9; 472.5) 35 371.3 (232.9; 511.2)COMP, UI/L (median (Q1, Q3)) 39 11.5 (9.6; 13.8) 35 10.9 (9.6; 12.9)HA, ng/mL (median (Q1, Q3)) 39 47.2 (35.8; 82.3) 35 47.9 (33.4; 67.4)hsCRP, mg/dL (median (Q1, Q3)) 39 0.9 (0.5; 2.0) 35 0.9 (0.4; 2.0)IL-1, pg/mL (median (Q1, Q3)) 24 0.1 (0.0; 0.3) 19 0.1 (0.0; 0.2)IL-6, pg/mL (median (Q1, Q3)) 39 0.8 (0.6; 1.3) 35 0.9 (0.7; 1.2)TNF α, pg/mL (median (Q1, Q3)) 38 0.9 (0.7; 1.3) 34 0.9 (0.5;1.3)

Results are presented as mean (SD), median (Q1, Q3) or n (%).Values are median±IQR.N: correspond to available data; note that the number of 41 in adalimumab and 42 in the placebo groups differs from the flow chart where 42 and 43 patients were randomised buttwo patients were ruled out for from all statistical analysis because it was impossible to determine which treatment was finally received after allocation (mistake in treatment allocationdue to a computer glitch).CHFS, Cochin Hand Function Scale; COMP, cartilage oligomeric matrix protein; HA, hyaluronan, hsCRP, high-sensitivity C reactive protein; IL, interleukin; NSAIDs, non-steroidalanti-inflammatory drugs; OA, osteoarthritis; PIIANP, N-terminal propeptide of type IIA collagen; SYSADOA, Slow Acting Drugs in Osteo-Arthritis; TNF, tumour necrosis factor;VAS, Visual Analogue Scale.

Table 2 Results for efficacy outcome: percentage of patients with at least 50% improvement in pain from baseline to week 6 (W6) (primaryend point) and week 26 (W26)

N Adalimumab N Placebo Relative risk 95% CI p Value

W6Impute all missing as failures, n (%) 41 13 (31.7) 37 9 (24.3) 1.10 0.82 to 1.49 0.51Impute all missing as success, n (%) 41 17 (41.5) 37 13 (35.1) 1.11 0.82 to 1.52 0.50Exclusion of missing data, n (%) 37 13 (35.1) 33 9 (27.3) 1.13 0.82 to 1.55 0.47

W26Impute all missing as failures, n (%) 41 6 (14.6) 37 8 (21.6) 0.92 0.77 to 1.10 0.35Impute all missing as success, n (%) 41 12 (29.3) 37 12 (32.4) 0.95 0.70 to 1.31 0.77Exclusion of missing data, n (%) 35 6 (17.1) 33 8 (24.2) 0.91 0.74 to 1.14 0.41

Results expressed as number (proportion of successes), relative risk (adalimumab vs placebo) with 95% CI from a log binomial model generalised estimating equations model.95% CI, 95% CI of relative risk.

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adalimumab but there were no significant correlation (allp>0.05).

Adverse eventsThe rate of adverse events was similar between the two groups.Overall adverse event was 73.0% (27/37) in the placebo groupand 75.6% (31/41) in the adalimumab group. Severe adverseevents were reported in 5.4% (2/37) in the placebo group and9.8% (4/41) in the adalimumab group. There was no seriousevent related to subcutaneous injection of adalimumab, in

particular no serious infection in those non-immune-compromised patients. Pain related to subcutaneous injectionwas observed in six subcutaneous injections: three in theplacebo group and in three adalimumab subjects, and weredescribed as burning, pain or pruritus of minor or mildintensity.

DISCUSSIONThis RCT failed to demonstrate a greater efficacy of adalimu-mab (two injections at a 2-week interval) over placebo to

Table 3 Results for secondary efficacy outcome: estimate of least-squares mean change in outcomes from baseline to 6 or 26 weeks

Outcome Adalimumab Placebo Difference* (95% CI) p Value

Pain score (VAS; 0–100 mm)N 39 37Mean (SD) at baseline 66.7 (13.1) 63.6 (12.7) – –

Mean (SE) change from baseline to W6 (week 6) −19.3 (4.2) −16.8 (4.3) −2.5 (−14.0 to 9.0) 0.67Mean (SE) change from baseline to W26 (week 26) −12.4 (4.2) −11.0 (4.3) −1.4 (−13.0 to 10.1) 0.80

Morning stiffness (minutes)N 38 37Mean at baseline (SD) 44.0 (60.6) 34.9 (40.1) – –

Mean (SE) change from baseline to W6 −13.1 (6.4) −16.1 (6.5) 3.0 (−14.4 to 20.5) 0.73Mean (SE) change from baseline to W26 −13.5 (7.1) −7.8 (7.4) −5.8 (−25.6 to 14.1) 0.56

No of swollen joints (0–30)N 40 37Mean (SD) at baseline 6.3 (4.6) 5.7 (4.2) – –

Mean (SE) change from baseline to W6 −2.3 (0.4) −1.6 0.5) 0.7 (−1.9 to 0.5) 0.27Mean (SE) change from baseline to W26 −3.0 (0.5) −1.1 (0.5) −1.9 (−3.2 to −0.6) 0.0062

No of painful joints (0–30)N 40 37Mean (SD) at baseline 10.7 (6.3) 9.5 (6.3) – –

Mean (SE) change from baseline to W6 −4.1 (1.0) −3.7 (1.0) −0.5 (−3.3 to 2.4) 0.75Mean (SE) change from baseline to W26 −4.2 (1.1) −2.7 (1.1) −1.4 (−4.5 to 1.6) 0.35

No of painful IP joints under digital pressure (0–30)N 40 37Mean (SD) at baseline 13.1 (5.7) 13.4 (6.4) – –

Mean (SE) change from baseline to W6 −4.1 (1.0) −3.7 (1.0) −0.4 (−3.1 to 2.4) 0.80Mean (SE) change from baseline to W26 −3.6 (1.0) −2.7 (1.1) −0.9 (3.7 to 2.0) 0.55

Dreiser Index (0–30)N 40 37Mean (SD) at baseline (SD) 15.7 (6.7) 15.5 (6.0) – –

Mean (SE) change from baseline to W6 −2.2 (0.9) −1.9 (0.9) −0.3 (−2.7 to 2.2) 0.82Mean (SE) change from baseline to W26 −1.3 (1.0) −1.3 (1.0) 0.0 (−2.6 to 2.6) 1.00

CHFS score (0–90)N 40 37Mean (SD) at baseline 36.5 (21.6) 35.6 (18.5) – –

Mean (SE) change from baseline to W6 −4.0 (2.3) −3.2 (2.4) −0.8 (−7.3 to 5.7) 0.82Mean (SE) change from baseline to W26 −0.7 (2.6) −1.1 (2.7) 0.5 (−6.9 to 7.8) 0.90

Physician global assessment (VAS; 0–100 mm)N 37 36Mean (SD) at baseline (SD) 63.2 (13.1) 58.9 (12.0) – –

Mean (SE) change from baseline to W6 −13.1 (3.8) −14.9 (3.9) 5.2 (−8.7 to 12.3) 0.73Mean (SE) change from baseline to W26 −10.4 (4.4) −9.3 (4.6) −1.1 (−13.5 to 11.3) 0.86

Patient global assessment (VAS; 0–100 mm)N 39 37Mean (SD) at baseline (SD) 66.4 (17.9) 59.9 (16.4) – –

Mean (SE) change from baseline to W6 −22.6 (4.0) −16.7 (4.1) −5.9 (−16.9 to 5.1) 0.29Mean (SE) change from baseline to W26 −12.7 (4.2) −8.8 (4.3) −3.9 (−15.2 to 7.4) 0.49

Results are from mixed effects model for repeated measurements: model including terms for treatment group, centre, baseline value of the variable, time, and treatment-by-timeinteraction.*Adalimumab minus control.CHFS, Cochin Hand Function Scale; VAS, Visual Analogue Scale; IP, interphalangeal joint.

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alleviate pain in subjects with painful digital hand OA refractoryto both analgesics and NSAIDs. The main clinical outcome (%of patients with at least a 50% improvement in pain from base-line to 6 weeks) was not different between the adalimumab andplacebo groups (p=0.48). The level of difference in painchange on a VAS was −2.5 mm at W6, far below the level ofclinical relevance.33 34 Furthermore, there was no differencebetween the groups at any time point as shown in figure 2. In

addition, none of the secondary outcomes showed any signifi-cant difference between the groups. Analgesic intake did notdiffer between groups. All these data strongly suggest that painand disability in hand OA are not TNF α-dependant.

There was no epidemiological difference in the patient profilebetween the two groups at baseline that may explain this lack ofefficacy of TNF α blockers, with the exception of a slightlyhigher pain level in the adalimumab group (67 vs 63 mm in theplacebo group). However, all analyses were adjusted for thisbaseline level which therefore cannot explain the negative resultof this trial. Lack of difference between the two groups cannotbe explained by a low disease activity at baseline (pain wasaround 60 mm in both groups) or by an unexpected high levelof response in the placebo group (27% of responders corre-sponded closely well to our initial hypothesis of 30% of respon-ders). The placebo effect in patients with hand OA waspreviously reported to be very high, with an effect size of 0.8on pain.35 Otherwise, anti-TNF α therapy (limited to two injec-tions) was perfectly well tolerated.

The failure of TNF α blockers in painful hand OA may indi-cate that TNF α is not the right target in order to improvesymptoms in hand OA. Similarly, a small, open-label trial (12patients) with inflammatory hand OA who received six subcuta-neous injections of adalimumab every other week (12 weeks)failed to demonstrate any pain improvement.26

However, it could be assumed that TNF α blockers may bemore active in joints that are painful and swollen in keepingwith the pro-inflammatory role of TNF α in the synovial mem-brane.13 In a 1-year RCT, adalimumab reduced the number ofnew erosions only in the subset of patients with clinically

PlaceboAdalimumab

LS mean changefrom baseline

0

–10

–20

–30

0 2 4 6 10 14

Week

26

Figure 2 Pain score changes over time.

Table 4 Changes at week 6 in joint biomarkers, hsCRP andcytokines levels after treatment of hand osteoarthritis patients withplacebo or adalimumab

Adalimumab Placebo

p Value*n ΔMedian (Q1; Q3) n ΔMedian (Q1; Q3)

PIIANP, ng/mL 36 47.6 (−34.6; 167.0) 31 22.5 (−39.1; 119.0) 0.50uCTX-II/Creat 36 39.4 (−38.1; 75.2) 30 −5.9 (−59.2; 62.6) 0.61COMP, UI/L 36 −0.0 (−1.4; 0.9) 31 0.1 (−1.0; 1.1) 0.43HA, ng/mL 36 −0.4 (−13.5; 17.5) 31 5.3 (−13.6; 16.0) 0.42hsCRP, mg/dL 36 −0.0 (−0.6; 1.0) 31 0.0 (−0.2; 0.3) 0.58

IL-1, pg/mL 14 0.0 (−0.0; 0.1) 10 0.0 (−0.0; 0.1) 0.75IL-6, pg/mL 36 −0.1 (−0.4; 0.2) 31 −0.0 (−0.2; 0.3) 0.45TNF α, pg/mL 34 −0.1 (−0.3; 0.1) 28 0.0 (−0.2; 0.2) 0.13

Values are median±IQR.*Mann–Whitney test.COMP, cartilage oligomeric matrix protein; HA, hyaluronan, hsCRP, high-sensitivity Creactive protein; IL, interleukin; PIIANP, N-terminal propeptide of type IIA collagen;TNF, tumour necrosis factor.

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swollen IP joints at baseline.27 But, in our study, post hoc ana-lysis of the subgroup of patients with more than three swollenjoints at baseline did not predict any positive response to TNF ablockers on pain.

Another hypothesis could be that TNF α blockers may exert adifferential effect on pain and structure. In patients withrheumatoid arthritis, infliximab therapy compared with otherDMARDs reduced both the radiological progression of preva-lent hand OA and the incidence of hand OA.28 In contrast, in arecent 1-year placebo-controlled trial, adalimumab (40 mg everytwo weeks) failed to demonstrate a structural effect.27 Similarly,we did not observe any difference in the evolution of biomar-kers of cartilage turnover (CTX-II, PIIANP, HA and COMP) orin serum levels of pro-inflammatory cytokines and in hsCRP.

Our study has several limitations. Only two subcutaneousinjections of adalimumab could be regarded as insufficient toobserve any clinical benefit. However, administration ofanti-TNF in inflammatory arthritis such as PsA is marked by arapid response (starting after only two injections).24 In addition,long-term administration of adalimumab in hand OA failed todemonstrate any benefit and thus does not support a prolongedtreatment with anti-TNF α.27 The choice of high response(more than 50% of pain improvement) as the main criterionmight show a milder clinical response. This hypothesis is notconfirmed regarding the equivalence of pain improvement inboth groups.

Though the current study is negative and does not supportour initial expectation, we still need therapeutic solutions forthese patients. A recent survey showed that participantsdescribed a lack of help and information with regard to themanagement of their hand OA and described a lack of compre-hension from practitioners of the impact of hand OA in theirlife.11 12 This reaction is certainly intensified by the lack of anyefficient treatment.

Looking for new targets such as IL-1 or IL-6 should certainlybe investigated in the future before closing the door.36 Onebrief report on three patients indicated some beneficial resultswith IL-1 Ra in patients with painful hand OA.37

In a situation without gold-standard therapy, it is importantto continue to explore new therapies with a good benefit–riskbalance. The subgroup of patients with ‘inflammatory’ hand OAand swollen joints may represent the best population to targetin future clinical trials of future therapies.

Author affiliations1Department of Rheumatology, Henri Mondor Hospital, Creteil, France2INSERM, AP-HP (Assistance Publique des Hôpitaux de Paris), Hôpital Hôtel Dieu,Centre d’Epidémiologie Clinique, Univ. Paris Descartes, Sorbonne Paris Cité, Facultéde Médecine, Paris, France3Department of Rheumatology, Hopital Saint Antoine University Paris VI, Paris,France4Unité de Recherche Clinique, Hopital Henri Mondor, UPEC Paris XII5Laboratoire Synarc, Lyon, France6Department of Rheumatology, Hopital de l’Archet, University Nice, France7Department of Rheumatology, University Nantes, France8Department of Rheumatology, Hopital Trousseau, University Tours, France9Department of Rheumatology, Hopital Lapeyronnie, University Montpellier, France10Department of Rheumatology, Centre Hospitalier Universitaire de Besançon,Université de Franche-Comté, Besançon, University of Besancon, France11Department of Rheumatology, Hopital de la Conception, University of Marseille,France12Department of Rheumatology, Hopital Brabois, University of Nancy, France13Department of Rheumatology, Hopital La Pitié, University Paris VI, France14Université Paris Diderot, Assistance Publique-Hôpitaux de Paris, HôpitalLariboisière, Fédération de Rhumatologie, Paris, France

Acknowledgements We are grateful to the patients who agreed to be included inthis trial, and we thank all the co-investigators: Créteil: Fevre Claire, Farrenq Valérie;

Paris (Saint Antoine): Champey Julien; Lyon: Piperno Muriel; Nice: Allam Yacine,Euller Ziegler Liana; Nancy: Rat Anne-Christine, Sommier Jean-Phillipe; Nantes,Maugars yves; Tours: Mammou Saloua; Dijon: Piroth Christine; Marseille: LegréVirginie; Lille: Pouyol Francois, Flipo René-Marc, Montpellier: Gérard-Dran Delphine;Paris (Pitié-Salpêtrière): Banneville Béatrice, Inaoui Rachida; Paris (Bichat): MeyerOlivier, Ballard Magali; Poitiers: Solau-Gervais Elisabeth, Besancon: Wendling Daniel;Paris (Lariboisière): Peyr Olivier.

Contributors The study was designed by the academic investigators.Representatives of TAP collected the data, and statisticians at TAP conducted allstatistical analyses. All authors had access to the data and vouch for the veracityand completeness of the data and the data analysis. The manuscript was written inits entirety by the authors.

Funding Sponsored by Hopitaux de Paris direction de la Recherche Clinique (DRC)(Hospitals of Paris, Clinical Research Department), St Louis, Paris (AssistancePublique-Hopitaux de Paris (APHP)) and supported by the Inserm Pro A. Abbot grantwhich was given with the agreement of the sponsor the DRC APHP, URC Mondor,but Abbot was not involved in the design, implementation and results of the study,which was performed independently of the firm.

Patient consent Obtained.

Ethics approval Independent Ethics Committees from Henri Mondor Hospital(Creteil, France).

Provenance and peer review Not commissioned; externally peer reviewed.

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doi: 10.1136/annrheumdis-2014-205348 published online May 9, 2014Ann Rheum Dis

 X Chevalier, P Ravaud, E Maheu, et al. double-blind, placebo-controlled trialNSAIDs: a randomised, multicentre,osteoarthritis refractory to analgesics and Adalimumab in patients with hand

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