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Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial
  1. Anna Tjärnlund1,
  2. Quan Tang1,
  3. Cecilia Wick1,
  4. Maryam Dastmalchi1,
  5. Herman Mann2,
  6. Jana Tomasová Studýnková2,
  7. Radka Chura3,
  8. Nicola J Gullick3,
  9. Rosaria Salerno3,
  10. Johan Rönnelid4,
  11. Helene Alexanderson5,
  12. Eva Lindroos1,
  13. Rohit Aggarwal6,
  14. Patrick Gordon3,
  15. Jiri Vencovsky2,
  16. Ingrid E Lundberg1
  1. 1 Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden
  2. 2 Department of Rheumatology, Institute of Rheumatology, Prague, Czech Republic
  3. 3 Department of Rheumatology, King’s College Hospital NHS Foundation Trust, London, UK
  4. 4 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
  5. 5 Division of Physiotherapy, Department of Neurobiology, Karolinska Institutet and Physical Therapy Clinic, Karolinska University Hospital, Stockholm, Sweden
  6. 6 Division of Rheumatology and Clinical Rheumatology, University of Pittsburgh School of Medicine, Pittsburgh, USA
  1. Correspondence to Anna Tjärnlund, Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden; anna.tjarnlund{at}


Objectives To study the effects of abatacept on disease activity and on muscle biopsy features of adult patients with dermatomyositis (DM) or polymyositis (PM).

Methods Twenty patients with DM (n=9) or PM (n=11) with refractory disease were enrolled in a randomised treatment delayed-start trial to receive either immediate active treatment with intravenous abatacept or a 3 month delayed-start. The primary endpoint was number of responders, defined by the International Myositis Assessment and Clinical Studies Group definition of improvement (DOI), after 6 months of treatment. Secondary endpoints included number of responders in the early treatment arm compared with the delayed treatment arm at 3 months. Repeated muscle biopsies were investigated for cellular markers and cytokines.

Results 8/19 patients included in the analyses achieved the DOI at 6 months. At 3 months of study, five (50%) patients were responders after active treatment but only one (11%) patient in the delayed treatment arm. Eight adverse events (AEs) were regarded as related to the drug, four mild and four moderate, and three serious AEs, none related to the drug. There was a significant increase in regulatory T cells (Tregs), whereas other markers were unchanged in repeated muscle biopsies.

Conclusions In this pilot study, treatment of patients with DM and PM with abatacept resulted in lower disease activity in nearly half of the patients. In patients with repeat muscle biopsies, an increased frequency of Foxp3+ Tregs suggests a positive effect of treatment in muscle tissue.

  • Dermatomyositis
  • polymyositis
  • treatment

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Dermatomyositis (DM) and polymyositis (PM) are chronic rheumatic diseases characterised by muscle weakness and low endurance. Other organs are often affected, such as skin in DM, but also lungs, joints and the gastrointestinal tract. Treatment of DM/PM includes high-dose glucocorticoids in combination with other immunosuppressive agents; however, effects are often disappointing and many patients are not able to regain muscle function.1 Health-related quality of life in patients with DM and PM is low compared with the general population.2 The majority of commonly used drugs are not approved for myositis, and only few randomised controlled trials (RCTs) have been performed in this patient group. Thus, there is an unmet need for new therapies for these patients.

T cells likely play a role in the disease process in DM and PM indicated by the predominance of T cells in the inflammatory infiltrates in muscle biopsies.3 CD28 is a key costimulatory molecule that is constitutively expressed on naïve T cells and binds to B7-1 (CD80) and B7-2 (CD86). The cytotoxic T lymphocyte antigen-4 (CTLA-4) binds specifically to B7-1 and B7-2, and hence inhibits the CD28-mediated costimulation of T cells. CTLA-4, CD28, CD86 and CD40 have been demonstrated on inflammatory cells infiltrating muscle tissue in patients with DM and PM.4 Another study demonstrated expression of BB-1, a counter-receptor for CTLA-4 and CD28, on major histocompatibility complex (MHC) class I-expressing muscle fibres from PM muscle tissue.5 The BB-1-positive fibres bound strongly to CLTA-4 and CD28 on the invasive CD8+ T cells, indicating a functional role for these molecules in muscle inflammation.

Abatacept is a fully human fusion protein of CTLA-4 and the Fc portion of human IgG1. Treatment with abatacept in rheumatoid arthritis (RA) has been successful in reducing disease activity.6 7 There are a few case reports where off-label abatacept treatment in myositis has shown beneficial effects,8–11 but no RCT has been performed.

The aim of this study was to investigate the efficacy and safety of abatacept in patients with DM or PM refractory to conventional treatment using a randomised trial design with delayed start in one arm.12 We furthermore aimed to study the effects of abatacept on tissue cell phenotype and molecular expression in repeated muscle biopsies and correlate the molecular data to clinical outcome.

Patients and methods

Trial design

This was a phase IIb pilot study with a randomised delayed treatment design. Half of the patients were randomised to treatment with abatacept from week 0 (arm A) and half to start active treatment after 3 months (arm B)12 (figure 1A). The open-label study had no placebo, but the efficacy outcome assessors were blinded to treatment arm. The study (NCT01315938) was conducted at three sites (Karolinska University Hospital Stockholm, Sweden; King’s College Hospital NHS, London, UK; and the Institute of Rheumatology Prague, Prague, Czech Republic), and the institutional review board at each location approved the protocol. Written informed consent was obtained from each participant. The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice and applicable regulatory requirements. Randomisation was performed by an external monitor on the basis of random numbers generated by a computer program using global randomisation with the three sites and stratified by DM and PM.

Figure 1

(A) Schematic diagram of the design of the abatacept treatment in polymyositis and dermatomyositis trial. Participants were randomised to receive abatacept treatment immediately (arm A) or as delayed-onset after 3 months (arm B). Depicted (longitudinal arrows) are the intervals for infusions and visits for clinical evaluation. (B) Diagram on patient flow.


Eligible participants were between 18 and 80 years with confirmed diagnoses of DM or PM.13 14 (For detailed information on muscle biopsy features, autoantibodies and extramuscular manifestation in addition to skin rash, see online supplementary table 1.) Patients had active disease after treatment with glucocorticoids (≥0.5 mg/kg/day for ≥1 month), in combination with at least one other immunosuppressive drug, methotrexate (minimum dose 15 mg/week) or azathioprine (minimum dose 100 mg/day) for at least 3 months. Concomitant methotrexate or azathioprine was allowed, with stable doses for ≥1 month prior to inclusion in the study. Active disease was defined as persisting or worsening muscle weakness (Manual Muscle Test (MMT)-8 bilaterally <150) or low endurance measured by Functional Index for myositis (FI-2) <20% of upper value,15 together with at least one other sign of active disease: elevated (above upper limit of normal) serum levels of muscle enzymes, inflammation in a recent muscle biopsy (<1 month) or on MRI findings consistent with inflammation, or active extramuscular disease. Inclusion and exclusion criteria are shown in online supplementary material 1 and 2).

Supplementary file 1


Abatacept was administered intravenously at a dose based on body weight at the screening visit: participants weighing <60 kg received 500 mg, 60–100 kg received 750 mg and those >100 kg received 1000 mg. Participants were treated with abatacept for 6 months and received a total of seven intravenous infusions at weeks 0, 2, 4, 8, 12, 16 and 20 (arm A) or at weeks 12, 14, 16, 20, 24, 28 and 32 (arm B).


The primary endpoint was the number of responders, defined according to the International Myositis Assessment and Clinical Studies Group (IMACS) preliminary definition of improvement (DOI),16 after treatment with abatacept for 6 months. IMACS DOI is defined as relative improvement by ≥20% in three of any six core set measures, with no more than two core set measures worsening by ≥25%, which cannot be MMT.

Secondary objectives included the number of responders in the delayed-onset arm compared with active treatment arm at 3 and 6 months, and the change in individual components of the IMACS core set measures for disease activity and in the muscle endurance as tested by FI-2, in the delayed-onset arm compared with active treatment arm at 3 and 6 months. The efficacy on the individual components of the IMACS core set measures, muscle endurance tested by FI-2, health-related quality of life assessed by Short Form-36 (SF-36) and signs of inflammation in muscle tissue (repeated muscle biopsies) were assessed after 6 months of active treatment. Worsening according to IMACS criteria (see online supplementary material 3) was assessed after 6 months of active treatment.

As a post-hoc analysis we applied the new myositis response criteria.17 We compared the median total improvement score (0–100) achieved by patients in study arm A versus study arm B at 3, 6 and 9 months’ time points. We also reported the frequency of patients meeting minimal, moderate and major improvement using thresholds of ≥20, 40 and 60, respectively, on total improvement scores at each time points.

Efficacy was assessed by a physician and physical therapist both blinded to the treatment arm the patients had been randomised to. Safety was assessed at every visit by the safety assessors based on clinical and laboratory examinations. The safety assessors determined any relatedness of adverse events (AE) or serious AE (SAE), categorised into mild, moderate or severe, to the study drug.

Muscle biopsies and immunohistochemistry

Muscle biopsies taken before and after 6 months of abatacept treatment in six patients were immunohistochemically stained for cellular markers and cytokines CD3, CD4, CD8, Foxp3, Ki67, CD68, CD19, CD20, CD31, DC-LAMP-PE, CD163, CTLA-4, CD244, interleukin-15, tumour necrosis factor-α and MHC class I (for details see online supplementary material 4 and online supplementary table 2).

Autoantibody testing

Patients sera taken before and after 6 months of treatment were analysed for presence of autoantibodies against Jo-1, SRP, Mi-2, PM/Scl 70, PM/Scl 75, PM/Scl 100, PL7, PL12, EJ, OJ, NXP2, TIF1-γ, SAE, MDA5, Ku and Ro52 using a validated line immunoassay system line blot (Euroimmun, Lübeck, Germany), according to the manufacturer’s instruction. Additional autoantibody data were retrieved retrospectively from the EuroMyositis registry and from medical records.

Statistical analysis

This was a pilot study. The response rate on which to base power calculations was unknown; hence the study was not powered to confirm efficacy. Based on feasibility considerations, it was estimated that 20 patients (10 DM; 10 PM) could be included at the three sites.

Baseline characteristics were summarised by randomised group and are presented as mean and SD for continuous (approximate) normally distributed variables, medians and IQRs for non-normally distributed variables, and frequencies and percentages for categorical variables. The significance of difference in the number of patients achieving DOI in each study arm at specified time points was compared using Fisher’s exact test. Continuous variables between the two arms at 3 and 6 months were analysed using the Student’s t-test if (approximate) normally distributed, or rank-sum, non-parametric test for non-normally distributed variables. Post-treatment versus pretreatment biopsies were compared using Wilcoxon matched-pairs signed-rank test. Analysis of the primary endpoint was based on the intention-to-treat (ITT) principle, applying non-responder imputation, where ITT population was defined as all patients who were randomised, and provided at least one baseline and corresponding postbaseline efficacy measurement. Analysis of secondary endpoints used last observation carried forward for continuous variables, in addition to the per-protocol principle.


The date of first patient visit was 2 March 2011, and the date of last patient visit was 28 November 2013. Out of 23 screened patients, 20 were randomised (figure 1B). One patient randomised to the delayed-onset arm (arm B) was changed to arm A to receive study drug earlier due to aggressive progress of weakness, in accordance with the study protocol. At study start there were 11 patients in arm A with immediate treatment, and nine in arm B the delayed-onset arm. One patient in study arm A was withdrawn from study after the first infusion due to rapidly progressive muscle weakness resulting in no postbaseline efficacy assessments; according to the protocol this patient was not included in the ITT analysis. Two patients in study arm B were withdrawn—one after the fourth infusion due to AE and another after the fifth infusion—because of worsening symptoms and withdrawal from the study by patient choice. These two patients were included in ITT considered as non-responders. Seventeen patients completed 9 months of the study.

Baseline characteristics are summarised in table 1. The two study arms were balanced, although the patients in arm A were significantly older than patients in arm B. No significant differences between patients from different sites were found. All patients had active disease with significant muscle weakness. Half of the patients had extramuscular organ involvement: interstitial lung disease (ILD), arthritis or dysphagia. Line blot analyses demonstrated autoantibody positivity for Jo-1 (n=6, 30%), PL-7 (n=1, 3%), PL-12 (n=1, 3%), Mi-2a (n=1, 3%), Mi-2b (n=1, 3%), SRP (n=2, 10%), TIF1-γ (n=2, 10%), NPX-2 (n=1, 3%), MDA5 (n=2, 10%), Ro52 (n=8, 40%) and Ku (n=1, 3%), with no significant differences between the groups (online supplementary table 3).

Table 1

Baseline characteristics of all patients enrolled in the study

Primary outcome

After 6 months of active treatment with abatacept, 8 out of 19 (42%) analysed (ITT) patients were classified as responders and reached the DOI, whereas 11 (58%) patients were non-responders (online supplementary table 1). Among responders, there were two patients with DM and six patients with PM, six women and two men. There were no statistically significant differences in numbers of DM/PM or female/male between responders and non-responders, nor were there differences in response rates between the different sites. Worsening was apparent for four patients, mainly due to worsening in extramuscular global disease activity (presented in online supplementary table 4).

Secondary outcomes

When comparing number of responders in the different arms after 3 months, when patients in arm A had been on active treatment for 3 months and patients in arm B had not yet started, there were five (50%) responders in arm A and 1 (11%) responder in arm B (p=0.1409). After 6 months, when patients in arm A had received active treatment for 6 months and patients in arm B had received active treatment for 3 months, there were six (60%) responders in arm A and one (11%) responder in arm B (p=0.0573).

Significant improvements in individual components of the IMACS core set measures could be seen for arm A compared with arm B at 3 and 6 months (table 2).

Table 2

Comparison of change in the individual components of the IMACS core set measures including the MYOACT of the MDAAT for the extramuscular disease activity at study months 3 and 6 (for Myositis Intention to Treat Activity Index (MITAX) score see online supplementary table 4

There was a significant improvement in muscle performance after 6 months of active treatment for the whole patient population, evidenced by the increase in MMT-8 and decrease in muscle disease activity (table 3). In addition, there was a numerical improvement in disease activity for all organ systems assessed. Myositis Intention to Treat Activity Index (MITAX) results are presented in online supplementary table 4.

Table 3

Median change in the individual components of the IMACS core set measures and extramuscular manifestations after active treatment for 6 months

The improvement on muscle performance measured by FI-2 after 6 months of active treatment was significant in number of repetitions for right shoulder flexion from a median (IQR) of 20 (17–70) to 37 (20–72) (p=0.0291), as well as for heel lift 25 (9–45) to 38 (13–66) (p=0.0103), with numerical improvement in all dimensions of FI-2. There was also significant improvement in the patient-reported outcome measures SF-36 in the physical component, with an increase from a median (IQR) of 31 (24–35) to 37 (24–45) (p=0.0054) after 6 months of active treatment.

We could not demonstrate a particular baseline phenotype that was associated with response to abatacept treatment.

Response using the new myositis response criteria

Total improvement score was significantly higher in study arm A at study month 3 as compared with study arm B (median, IQR) (28.8 (15–37.5) vs 5.0 (0–12.5), p=0.03) (figure 2). Similar trends were seen in median total improvement score in the two treatment groups at study months 6 and 9. In arm A, minimal improvement was achieved by 60%, 80% and 90% of the patients at 3, 6 and 9 months, respectively, whereas in arm B minimal improvement was achieved by 20%, 40% and 40% of the patients at 3, 6 and 9 months, respectively. Forty per cent of patients in arm A achieved moderate improvement compared to only 10% in arm B. No patient achieved major improvement at any time point.

Figure 2

Median total improvement score in patients with drug early (arm A, black line) versus drug late (arm B, red line) at study months 3, 6 and 9. The solid square (black) and solid round (red) are the median total improvement scores for drug early and drug late, respectively. Error bars denote the 25–75th interquartile values for the total improvement score.

Muscle biopsies

The expression of Foxp3 in muscle biopsies was significantly higher after compared with before abatacept treatment (p<0.05) (figure 3A). Other markers were unchanged after treatment, including CD3 expression (figure 3C). MMT-8 of the six patients with repeat biopsy was higher after 6 months of treatment but not statistically significant (median (IQR) 72.00 (60.25–74.00) vs 73.50 (66.00–78.50) (figure 3D).

Figure 3

Effect of abatacept treatment on histological markers and muscle strength of a subgroup of patients (n=6; 4 DM, 2 PM) with muscle biopsies taken before and after 6 months of abatacept treatment. (A) Foxp3 expression in muscle tissue of patients with DM and PM before and after treatment. (B) Representative image of Foxp3 immunohistochemical staining in muscle biopsy from a patient with DM. Magnification 25×. (C) CD3 expression in muscle tissue of patients with DM and PM before and after treatment. The positive expression of Foxp3 and CD4 was determined by computerised image analysis of whole muscle sections, Foxp3 expressed as the number of positive cells per tissue area, while CD3 expression was calculated as the percentage positively stained areas of the whole tissue area. (D) Muscle strength of patients with DM and PM using MMT-8. *p<0.05; ns, not statistically significant. DM, dermatomyositis; MMT-8, Manual Muscle Test-8; PM, polymyositis.


Autoantibody levels were unchanged after 6 months of abatacept treatment. One exception was a patient with borderline positive anti-MDA5 antibody before, but negative after treatment. There was no autoantibody positivity that was associated with clinical response or no response to treatment.


There were 36 AEs reported during the study, of which 8 were considered to be related to the study drug. Half of these AEs were mild and half were of moderate severity. There were no severe AEs. Out of the 28 reported AEs that were not related to the study drug, 17 were mild, 4 were moderate, 2 were severe, 4 were SAEs and 1 had no severity registered. The most common AEs reported were infections (n=14), followed by cardiovascular events (n=4), tumours (n=3), skin manifestations (n=3), musculoskeletal system effects (n=3), gastrointestinal effects/nausea (n=2), urinary tract effects (n=1), neuropathological effects (n=1) and other (n=5). The infections comprised upper respiratory tract (n=9), urinary tract (n=1), herpes zoster (n=1), left flank pain (n=1) and unspecified (n=2).


This was a pilot study to investigate the efficacy and safety of abatacept treatment in patients with DM and PM with persistent active disease after conventional immunosuppressive treatment. Although not powered to confirm efficacy, results revealed that almost half of the patients in this refractory population achieved clinically meaningful and statistically significant improvements. After 6 months of active treatment, 42% of patients were responders with lower disease activity according to the IMACS DOI, and significant improvement in muscle performance, evidenced by improved MMT-8 and decreased muscle disease activity, was demonstrated. These results were confirmed using the new response criteria for myositis.

Active treatment for 6 months revealed significantly improved muscle performance measured by MMT-8 and also in two of the subscales of the muscle endurance test FI-2. The clinical relevance of these improved measures is supported by the improved patient-reported outcome in the physical component of the health-related quality of life instrument. Long-term effectiveness of abatacept has been demonstrated in patients with RA, where the clinical efficacy increased with time even after 24 weeks.18 This was strongly linked to concomitant methotrexate use. In our trial methotrexate (minimum dose 15 mg/week) use was allowed concomitantly with study drug and was kept at a stable dose throughout the study period. Seventy-five per cent of responders and 36% of non-responders were on concomitant methotrexate.

A beneficial effect of abatacept on muscle performance was seconded by a higher expression of anti-inflammatory Foxp3regulatory T cells (Tregs) in muscle biopsies taken after compared with before 6 months of treatment. We have previously shown a decrease in number of Foxp3+ cells in the muscle tissue of patients with myositis  on treatment with glucocorticoids.19 This difference could be related to the different treatment targets since tissue-resident Foxp3+ Tregs have been implicated in muscle repair and regeneration.20 21 The effect of abatacept on Tregs is still unknown. Abatacept therapy in patients with RA has generated inconclusive results concerning the ability of abatacept to induce Treg cells and may reflect differences in different compartments, blood, synovial tissue or muscle.22–24 No differential expression in the other cell surface markers or cytokines analysed was detected in our study.

The safety profile with abatacept treatment in myositis revealed no new safety signals. The most commonly reported AE was infection in the upper respiratory tract, followed by cardiovascular effects, of which all were considered mild or moderate in severity.

This study was an open pilot study with a limited number of patients where we applied a novel study design, delayed-start design, to strengthen the data.12 We observed improvement in the active treatment arm compared with the delayed-start arm at 3 months. Although results are encouraging, future randomised placebo-controlled trials in larger patient populations are needed. Importantly, none of the patients in the study had characteristics of immune-mediated necrotising myopathy, although two had anti-signal recognition particle (SRP) antibodies. In this pilot study the major improvement was seen in muscle performance. There was improvement also in extramuscular domains—skeletal and cutaneous—although the improvement did not reach statistical significance.

Our results provide evidence that abatacept treatment is clinically efficacious in a subgroup of patients with DM or PM and has an acceptable safety profile in refractory patients. These results suggest that abatacept might provide a new treatment option in PM/DM and warrants further investigation.


We are grateful to Christina Ottosson for excellent coordination of study participants and administrative assistance. We also thank Eva Jemseby and Gull-Britt Almgren for outstanding handling and preparation of biological samples.



  • AT and QT contributed equally.

  • Handling editor Tore K Kvien

  • Contributors All authors were involved in drafting the article or revising it critically for important intellectual content. All authors approved the final version to be published and had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: AT, QT, CW, MD, HM, JTS, RC, NJG, RS, JR, HA, EL, RA, PG, JV, IEL. Acquisition of data: AT, QT, CW, MD, HM, JTS, RC, NJG, RS, JR, HA, EL, RA, PG, JV, IEL. Analysis and interpretation of data: AT, QT, CW, MD, HM, JTS, RC, NJG, RS, JR, HA, EL, RA, PG, JV, IEL. AT and QT contributed equally to this paper.

  • Funding This study was carried out as an investigator-initiated study funded by a grant from Bristol-Myers Squibb (BMS) and Börje Dahlin Foundation, Swedish Research Council GRANTK2014-52X-14045-14-3, Swedish Rheumatism Association, King Gustaf V 80-Year Foundation, and the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet. BMS provided the study drug. The presented work was initiated, conducted and performed independently of BMS.

  • Competing interests IEL: research grant and advisory board consultant for BMS, research grant from AstraZeneca, consultant for MedImmune, aTyr and IDERA. RA: research grant from BMS.

  • Patient consent Obtained.

  • Ethics approval The institutional review board at each study site.

  • Provenance and peer review Not commissioned; externally peer reviewed.