Randomized Trial of Tocilizumab in the Treatment of Refractory Adult Polymyositis and Dermatomyositis.

OBJECTIVE: To assess the efficacy and tolerability of tocilizumab in a multicenter, randomized, double-blind, placebo-controlled trial in refractory adult patients with dermatomyositis (DM) and polymyositis (PM). METHODS: Thirty-six subjects with probable or definite DM/PM were enrolled in a 6-month phase 2B clinical trial and randomized 1:1 to receive tocilizumab (8 mg/kg intravenously) or placebo every 4 weeks for 24 weeks. Eligible subjects had either a DM rash, a myositis-associated autoantibody or an adjudicated PM diagnosis. Active disease was defined by at least three of six abnormal core set measures (CSMs), including a manual muscle testing (MMT)-8 score of less than 136/150. If the MMT-8 score was greater than 136, then a cutaneous score of 3 or more (10 cm visual analogue scale) was required along with three additional abnormal CSMs indicating disease activity. The primary endpoint compared the Total Improvement Score (TIS) between both arms from week 4 to 24. Secondary outcomes included time to meeting minimal TIS improvement, changes in CSMs, time to worsening, steroid-sparing effect, proportion of subjects meeting more stringent improvement criteria, and safety outcomes. RESULTS: There was no significant difference (P = 0.86) in the TIS over 24 weeks between tocilizumab and placebo arms. The secondary endpoints of time to improvement (minimal, moderate, or major), time to worsening, CSM changes, safety outcomes, and steroid-sparing effect were also not significantly different between arms. CONCLUSION: Tocilizumab was safe and well tolerated but did not meet the primary or secondary efficacy outcomes in refractory DM and PM in this 24-week phase 2B study.

Consumer-based activity trackers in evaluation of physical activity in myositis patients.

OBJECTIVES: Inflammatory myopathies are characterized by muscle weakness that limits the activities of daily living. Daily step count is an accepted metric of physical activity. Wearable technologies such as Fitbit® enable tracking of daily step counts. We assessed the psychometric properties of Fitbit® and compared the accuracy of Fitbit® step counts to ActiGraph®. METHODS: This was a pilot, proof of concept, prospective observational study with four visits at 0, 1, 3 and 6 months in PM, DM, necrotizing myopathy (NM) or anti-synthetase syndrome (AS) subjects. Six core set measures (manual muscle testing, physician global disease activity, patient global disease activity, and extra-muscular disease activity, HAQ-Disability Index and creatine kinase), three functional tests (six-min walk, timed up-and-go, sit-to-stand tests) and SF-36 physical function-10 (PF10) were collected at each visit. Patients wore waist-worn Fitbit® One and ActiGraph® T3X-BT concurrently for 7 days/month for 6 months. RESULTS: Twenty-four (10 DM, 8 PM/NM, 6 AS) patients (17 females/7 males; 91% Caucasian) were enrolled. Test-retest reliability of daily steps was strong in 1-month follow-up (ICC 0.89). Daily steps and peak 1-min cadence showed moderate-strong correlations with physician global disease activity, patient global disease activity, HAQ-Disability Index, SF-36 PF10 and all three functional tests. Fitbit® and ActiGraph® step counts demonstrated good agreement and strong correlation (ICC 0.96). CONCLUSION: Fitbit® daily steps and peak 1-min cadence are reliable and valid measures of physical activity in a cohort of myositis patients. This pilot data suggests that Fitbit® has a potential for use in clinical practice and trials to monitor physical activity in myositis patients, but larger studies are needed for further validation.

Utility of patient-reported outcomes measurement information system (PROMIS) physical function form in inflammatory myopathy.

OBJECTIVE: Idiopathic inflammatory myopathies (IIM) are a group of diseases characterized by muscle weakness, which limit activities of daily living. Patient Reported Outcomes Measurement Information System (PROMIS) is a set of outcome measures developed using NIH funding, but has not yet been studied in adult IIM. Currently, the most commonly used PROs in IIM are Health Assessment Questionnaire (HAQ-DI) and SF-36 physical function-10 (PF10), both of which have several limitations. In this study, we investigated psychometric properties of PROMIS physical function-20 (PF-20) and compared to HAQ-DI and SF-36 PF10. METHODS: Patients with IIM completed PROMIS PF-20 and six myositis core set measures [manual muscle testing (MMT), physician (MD-GDA), patient (PT-GDA) and extra-muscular global disease activity, HAQ-DI and creatine kinase], SF-36 PF10 and functional tests [six-minute walk, timed up-and-go and sit-to-stand tests] at monthly visits over 6-months. Total improvement score (TIS) using 2016 ACR/EULAR myositis response criteria was obtained as measures of change. RESULTS: Fifty patients [mean age, 51.6; 60% females] were enrolled; 6 PM, 24 DM, 9 NM and 11 with AS. PROMIS PF-20 showed strong test-retest reliability when repeated in 1-month. PROMIS PF-20 had moderate-strong correlations with MD-GDA, PT-GDA, MMT, HAQ-DI, SF-36 PF10, and functional tests indicating good convergent validity. Change in PROMIS PF-20 strongly correlated with TIS demonstrating good responsiveness. HAQ-DI and SF-36 PF10 exhibited similar validity and responsiveness; HAQ-DI was found to have a ceiling effect. CONCLUSION: PROMIS PF-20 demonstrates favorable psychometric properties in a large cohort of myositis patients and offers distinct advantages.

Reliability, validity and responsiveness of physical activity monitors in patients with inflammatory myopathy.

OBJECTIVE: Idiopathic inflammatory myopathies (IIMs) cause proximal muscle weakness, which affects the ability to carry out the activities of daily living. Wearable physical activity monitors (PAMs) objectively assess continuous activity and potentially have clinical usefulness in the assessment of IIMs. We examined the psychometric characteristics for PAM outcomes in IIMs. METHODS: Adult IIM patients were prospectively evaluated (at baseline, 3 months and 6 months) in an observational study. A waist-worn PAM (ActiGraph GT3X-BT) assessed average step counts/minute, peak 1-minute cadence, and vector magnitude/minute. Validated myositis core set measures (CSMs) including manual muscle testing (MMT), physician global disease activity (MD global), patient global disease activity (Pt global), extramuscular disease activity (Ex-muscular global), HAQ-DI (HAQ disability index), muscle enzymes, and patient-reported physical function were evaluated. Test-retest reliability, construct validity, and responsiveness were determined for PAM measures and CSMs, using Pearson correlations and other appropriate analyses. RESULTS: A total of 50 adult IIM patients enrolled [mean (s.d.) age, 53.6 (14.6); 60% female, 94% Caucasian]. PAM measures showed strong test-retest reliability, moderate-to-strong correlations at baseline with MD global (r = -0.37 to -0.48), Pt global (r=-0.43 to -0.61), HAQ-DI (r = -0.47 to -0.59) and MMT (r = 0.37-0.52), and strong discriminant validity for categorical MMT and HAQ-DI. Longitudinal associations with MD global (r=-0.38 to -0.44), MMT (r = 0.50-0.57), HAQ-DI (r = -0.45 to -0.55) and functional tests (r = 0.30-0.65) were moderate to strong. PAM measures were responsive to MMT improvement ≥10% and moderate-to-major improvement on ACR/EULAR myositis response criteria. Peak 1-minute cadence had the largest effect size and standardized response means. CONCLUSION: PAM measures showed promising construct validity, reliability, and longitudinal responsiveness; especially peak 1-minute cadence. PAMs are able to provide valid outcome measures for future use in IIM clinical trials.

A Pilot Study of Dimethyl Fumarate in Pulmonary Arterial Hypertension Associated with Systemic Sclerosis.

INTRODUCTION: Given the poor treatment options for pulmonary arterial hypertension associated systemic sclerosis (SSc-PAH) patients, we sought to determine clinical safety and efficacy of Dimethylfumarate (DMF), an Nrf2 agonist, and the effects on biomarkers of oxidative stress on SSc-PAH in an exploratory interventional clinical trial. OBJECTIVES: The primary objectives were to assess the safety and efficacy of treatment with DMF in patients with SSc-PAH. METHODS: This was an investigator-initiated, double-blind, randomized, placebo-controlled trial conducted at two sites in the United States. The primary safety endpoint was the incidence of serious adverse events (SAEs) and all adverse events (AEs) in DMF compared to placebo-treated patients. The primary efficacy endpoint was the change in 6MWD from baseline to the end of treatment at Week 24 in DMF compared to placebo-treated patients. RESULTS: Six participants were randomized to either placebo (n = 2) or DMF (n = 4). Baseline demographics were similar in both groups. A total of 25 adverse events (AEs) occurred in 6 subjects, with 14 AEs (56.0%) having occurred in DMF-treated subjects. 3 occurrences were identified as nausea AEs, and two participants withdrew due to nausea. One participant in the placebo group was withdrawn after a hospitalization SAE due to worsening of heart failure and shortness of breath secondary to anemia. One participant in each group completed protocol. Subjects in the DMF-treated group showed a non-significant reduced decline in 6MWD (relative mean change of -7.07%) from baseline to Week 24 as compared to placebo-treated subjects (relative mean change of -14.97%). CONCLUSION: Patients treated for SSc-PAH with 2 and 3-drug regimens, as is now typical for these patients, tolerate DMF poorly. Our small samples size did not provide power to suggest efficacy. We suggest that Nrf2 is still a valid therapeutic target for future trials, using better tolerated Nrf2 agonists.

Hand-held dynamometry for assessment of muscle strength in patients with inflammatory myopathies.

OBJECTIVES: Muscle weakness in idiopathic inflammatory myopathies (IIMs) is conventionally assessed using manual muscle testing (MMT). However, more objective tools must be developed to accurately and reliably quantify muscle strength in myositis patients. Hand-held dynamometry (HHD) is a quantitative, portable device with reported reliability in neuromuscular disorders. Our aim was to assess the reliability, validity and responsiveness of HHD in myositis. METHODS: Myositis patients [DM, necrotizing myopathy (NM), PM and anti-synthetase syndrome] evaluated at the University of Pittsburgh myositis centre were prospectively enrolled. Each patient was assessed at 0, 3 and 6 months for validated outcome measures of myositis disease activity and physical function. At each visit, muscle strength was assessed using both MMT and HHD (Micro FET2, Hoggan Health Industries, Draper, UT, USA). The reliability, validity and responsiveness of the HHD was assessed using standard statistical methods. RESULTS: Fifty IIM patients (60% female; mean age 51.6 years; 6 PM, 9 NM, 24 DM and 11 anti-synthetase syndrome) were enrolled. HHD showed strong test-retest intrarater reliability (r = 0.96) and interrater reliability (r = 0.98). HHD correlated significantly with the MMT score (r = 0.48, P = 0.0006) and myositis disease activity and functional measures. Longitudinal analysis showed a significant and strong association between the HHD and MMT as well as 2016 ACR/EULAR myositis response criteria (r = 0.8, P < 0.0001) demonstrating responsiveness. The mean effect size and standardized response mean of HHD was large: 0.95 and 1.03, respectively. MMT had a high ceiling effect compared with HHD. CONCLUSION: HHD demonstrated strong reliability, construct validity and responsiveness in myositis patients. External validation studies are required to confirm these findings.

Follow-up results of myositis patients treated with H. P. Acthar gel.

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by proximal muscle weakness. H. P. Acthar gel [repository corticotropin injection (RCI)] is a formulation of adrenocorticotropic hormone and has been approved by Food and Drug Administration for use in IIM; however, literature is limited. In this study, we report longitudinal follow-up of myositis patients treated with RCI. METHODS: Patients with refractory IIM who were enrolled in the prospective, open-label RCI trial were included in this study. The post-trial follow-up period was 6 months with assessments every 2 months, which included myositis core set measures including extra-muscular global, muscle and patient global disease activities, HAQ, and manual muscle testing. RESULTS: Two patients were lost to follow-up after finalization of the trial, and the remaining eight patients were enrolled in the follow-up study. One patient remained on RCI after the trial. In the follow-up period, four of eight patients had flare at on average 4.1 months after the RCI trial. Among the patients who flared, three required an increase in prednisone. One patient was restarted on RCI at 5.5 months, but had minimal improvement after 3 months. Four patients who remained stable continued to satisfy criteria for the definition of improvement through the 6-month follow-up. However, none showed any further improvement in the primary or secondary efficacy outcomes after the initial RCI trial. CONCLUSION: To our knowledge, this is the first study reporting the follow-up results of patients treated with standard dose and duration of Acthar. We believe that our study will provide the basis for the development of future randomized RCI trials in IIM.

Rituximab in the Treatment of Interstitial Lung Disease Associated with Antisynthetase Syndrome: A Multicenter Retrospective Case Review.

OBJECTIVE: To assess clinical outcomes including imaging findings on computed tomography (CT), pulmonary function testing (PFT), and glucocorticoid (GC) use in patients with the antisynthetase syndrome (AS) and interstitial lung disease (ILD) treated with rituximab (RTX). METHODS: We retrospectively identified all patients at 2 institutions with AS-ILD who were treated with RTX. Baseline demographics, PFT, and chest CT were assessed before and after RTX. Two radiologists independently evaluated CT using a standardized scoring system. RESULTS: Twenty-five subjects at the Brigham and Women's Hospital (n = 13) and University of Pittsburgh Medical Center (n = 12) were included. Antisynthetase antibodies were identified in all patients (16 Jo1, 6 PL-12, 3 PL-7). In 21 cases (84%), the principal indication for RTX use was recurrent or progressive ILD, owing to failure of other agents. Comparing pre- and post-RTX pulmonary variables at 12 months, CT score and forced vital capacity were stable or improved in 88% and 79% of subjects, respectively. Total lung capacity (%) increased from 56 ± 13 to 64 ± 13 and GC dose decreased from 18 ± 9 to 12 ± 12 mg/day. Although DLCO (%) declined slightly at 1 year, it increased from 42 ± 17 to 70 ± 20 at 3 years. The most common imaging patterns on CT were nonspecific interstitial pneumonia (NSIP; n = 13) and usual interstitial pneumonia/fibrotic NSIP (n = 5), of which 5 had concurrent elements of cryptogenic organizing pneumonia. CONCLUSION: Stability or improvement in pulmonary function or severity of ILD on CT was seen in most patients. Use of RTX was well tolerated in the majority of patients. RTX may play a therapeutic role in patients with AS-ILD, and further clinical investigation is warranted.

Efficacy and safety of adrenocorticotropic hormone gel in refractory dermatomyositis and polymyositis.

AIM: To evaluate the efficacy, safety, tolerability and steroid-sparing effect of repository corticotropin injection (RCI), in an open-label clinical trial, in refractory adult polymyositis (PM) and dermatomyositis (DM). METHODS: Adults with refractory PM and DM were enrolled by two centres. Inclusion criteria included refractory disease defined as failing glucocorticoid and/or ≥1 immunosuppressive agent, as well as active disease defined as significant muscle weakness and >2 additional abnormal core set measures (CSMs) or a cutaneous 10 cm Visual Analogue Scale score of ≥3 cm and at least three other abnormal CSMs. All patients received RCI of 80 units subcutaneously twice weekly for 24 weeks. The primary end point for the trial was the International Myositis Assessment and Clinical Studies definition of improvement. Secondary end points included safety, tolerability, steroid-sparing as well as the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism myositis response criteria (EULAR) RESULTS: Ten of the 11 enrolled subjects (6 DM, 4 PM) completed the study. Seven of 10 met the primary end point of efficacy at a median of 8 weeks. There was a significant decrease in prednisone dose from baseline to conclusion (18.5 (15.7) vs 2.3 (3.2); P<0.01). Most individual CSMs improved at week 24 compared with the baseline, with the muscle strength improving by >10% and the physician global by >40%. RCI was considered safe and tolerable. No patient developed significant weight gain or an increase of haemoglobin A1c or cushingoid features. CONCLUSION: Treatment with RCI was effective in 70% of patients, safe and tolerable, and led to a steroid dose reduction in patients with adult myositis refractory to glucocorticoid and traditional immunosuppressive drugs. TRIAL REGISTRATION NUMBER: NCT01906372; Results.

A Negative Antinuclear Antibody Does Not Indicate Autoantibody Negativity in Myositis: Role of Anticytoplasmic Antibody as a Screening Test for Antisynthetase Syndrome.

OBJECTIVE: To evaluate the utility of anticytoplasmic autoantibody (anti-CytAb) in antisynthetase antibody-positive (anti-SynAb+) patients. METHODS: Anti-SynAb+ patients were evaluated for antinuclear antibody (ANA) and anti-CytAb [cytoplasmic staining on indirect immunofluorescence (IIF)] positivity. Anti-SynAb+ patients included those possessing anti-Jo1 and other antisynthetase autoantibodies. Control groups included scleroderma, systemic lupus erythematosus, Sjögren syndrome, rheumatoid arthritis, and healthy subjects. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy of anti-CytAb, and ANA were assessed. Anti-CytAb and ANA testing was done by IIF on human epithelial cell line 2, both reported on each serum sample without knowledge of the clinical diagnosis or final anti-SynAb results. RESULTS: Anti-SynAb+ patients (n = 202; Jo1, n = 122; non-Jo1, n = 80) between 1985-2013 with available serum samples were assessed. Anti-CytAb showed high sensitivity (72%), specificity (89%), NPV (95%), and accuracy (86%), but only modest PPV (54%) for anti-SynAb positivity. In contrast, ANA showed only modest sensitivity (50%) and poor specificity (6%), PPV (9%), NPV (41%), and accuracy (12%). Positive anti-CytAb was significantly greater in the anti-SynAb+ patients than ANA positivity (72% vs 50%, p < 0.001), and 81/99 (82%) ANA-negative patients in the anti-SynAb+ cohort had positive anti-CytAb. In contrast, the control groups showed high rates for ANA positivity (93.5%), but very low rates for anti-CytAb positivity (11.5%). Combining anti-CytAb or Jo1 positivity showed high sensitivity (92%) and specificity (89%) for identification of anti-SynAb+ patients. CONCLUSION: Assessing patients for anti-CytAb serves as an excellent screen for anti-SynAb+ patients using simple IIF. Cytoplasmic staining should be assessed and reported for patients suspected of having antisynthetase syndrome and a negative ANA should not be used to exclude this diagnosis.

Cutaneous improvement in refractory adult and juvenile dermatomyositis after treatment with rituximab.

OBJECTIVE: The aim was to assess the efficacy of rituximab for the cutaneous manifestations of adult DM and JDM. METHODS: Patients with refractory adult DM (n = 72) and JDM (n = 48) were treated with rituximab in a randomized placebo-phase-controlled trial [either rituximab early drug (week 0/1) or rituximab late arms (week 8/9), such that all subjects received study drug]. Stable concomitant therapy was allowed. Cutaneous disease activity was assessed using the Myositis Disease Activity Assessment Tool, which grades cutaneous disease activity on a visual analog scale. A myositis damage assessment tool, termed the Myositis Damage Index, was used to assess cutaneous damage. Improvement post-rituximab was evaluated in individual rashes as well as in cutaneous disease activity and damage scores. The χ2 test, Student's paired t-test and Wilcoxon test were used for analysis. RESULTS: There were significant improvements in cutaneous disease activity from baseline to the end of the trial after rituximab administration in both adult DM and JDM subsets. The cutaneous visual analog scale activity improved in adult DM (3.22-1.72, P = 0.0002) and JDM (3.26-1.56, P <0.0001), with erythroderma, erythematous rashes without secondary changes of ulceration or necrosis, heliotrope, Gottron sign and papules improving most significantly. Adult DM subjects receiving rituximab earlier in the trial demonstrated a trend for faster cutaneous response (20% relative improvement from baseline) compared with those receiving B cell depletion later (P = 0.052). CONCLUSION: Refractory skin rashes in adult DM and JDM showed improvement after the addition of rituximab to the standard therapy in a clinical trial.

Autoantibody levels in myositis patients correlate with clinical response during B cell depletion with rituximab.

OBJECTIVES: To determine the longitudinal trends in serum levels of four myositis-associated autoantibodies: anti-Jo-1, -transcription intermediary factor 1 γ (TIF1-γ), -signal recognition particle (SRP) and -Mi-2, after B cell depletion with rituximab, and to determine the longitudinal association of these autoantibody levels with disease activity as measured by myositis core-set measures (CSMs). METHODS: Treatment-resistant adult and pediatric myositis subjects (n = 200) received rituximab in the 44-week Rituximab in Myositis Trial. CSMs [muscle enzymes, manual muscle testing (MMT), physician and patient global disease activity, HAQ, and extramuscular disease activity] were evaluated monthly and anti-Jo-1 (n = 28), -TIF1-γ (n = 23), -SRP (n = 25) and -Mi-2 (n = 26) serum levels were measured using validated quantitative ELISAs. Temporal trends and the longitudinal relationship between myositis-associated autoantibodies levels and CSM were estimated using linear mixed models. RESULTS: Following rituximab, anti-Jo-1 levels decreased over time (P < 0.001) and strongly correlated with all CSMs (P < 0.008). Anti-TIF1-γ levels also decreased over time (P < 0.001) and were only associated with HAQ, MMT and physician and patient global disease activity. Anti-SRP levels did not change significantly over time, but were significantly associated with serum muscle enzymes. Anti-Mi-2 levels significantly decreased over time and were associated with muscle enzymes, MMT and the physician global score. CONCLUSION: Anti-Jo-1, anti-TIF1-γ and anti-Mi-2 levels in myositis subjects decreased after B cell depletion and were correlated with changes in disease activity, whereas anti-SRP levels were only associated with longitudinal muscle enzyme levels. The strong association of anti-Jo-1 levels with clinical outcomes suggests that anti-Jo-1 autoantibodies may be a good biomarker for disease activity.

Detection of Rheumatoid Arthritis-Interstitial Lung Disease Is Enhanced by Serum Biomarkers.

RATIONALE: Interstitial lung disease (ILD), a leading cause of morbidity and mortality in rheumatoid arthritis (RA), is highly prevalent, yet RA-ILD is underrecognized. OBJECTIVES: To identify clinical risk factors, autoantibodies, and biomarkers associated with the presence of RA-ILD. METHODS: Subjects enrolled in Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study (BRASS) and American College of Rheumatology (ACR) cohorts were evaluated for ILD. Regression models were used to assess the association between variables of interest and RA-ILD. Receiver operating characteristic curves were generated in BRASS to determine if a combination of clinical risk factors and autoantibodies can identify RA-ILD and if the addition of investigational biomarkers is informative. This combinatorial signature was subsequently tested in ACR. MEASUREMENTS AND MAIN RESULTS: A total of 113 BRASS subjects with clinically indicated chest computed tomography scans (41% with a spectrum of clinically evident and subclinical RA-ILD) and 76 ACR subjects with research or clinical scans (51% with a spectrum of RA-ILD) were selected. A combination of age, sex, smoking, rheumatoid factor, and anticyclic citrullinated peptide antibodies was strongly associated with RA-ILD (areas under the curve, 0.88 for BRASS and 0.89 for ACR). Importantly, a combinatorial signature including matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly increased the areas under the curve to 0.97 (P = 0.002, BRASS) and 1.00 (P = 0.016, ACR). Similar trends were seen for both clinically evident and subclinical RA-ILD. CONCLUSIONS: Clinical risk factors and autoantibodies are strongly associated with the presence of clinically evident and subclinical RA-ILD on computed tomography scan in two independent RA cohorts. A biomarker signature composed of matrix metalloproteinase 7, pulmonary and activation-regulated chemokine, and surfactant protein D significantly strengthens this association. These findings may facilitate identification of RA-ILD at an earlier stage, potentially leading to decreased morbidity and mortality.

Anti-signal recognition particle autoantibody ELISA validation and clinical associations.

OBJECTIVE: The aim of this study was to develop and validate a quantitative anti-signal recognition particle (SRP) autoantibody serum ELISA in patients with myositis and longitudinal association with myositis disease activity. METHODS: We developed a serum ELISA using recombinant purified full-length human SRP coated on ELISA plates and a secondary antibody that bound human IgG to detect anti-SRP binding. Protein immunoprecipitation was used as the gold standard for the presence of anti-SRP. Serum samples from three groups were analysed: SRP(+) myositis subjects by immunoprecipitation, SRP(-) myositis subjects by immunoprecipitation and non-myositis controls. The ELISA's sensitivity, specificity, positive predictive value and negative predictive value were evaluated. Percentage agreement and test-retest reliability were assessed. Serial samples from seven SRP immunoprecipitation-positive subjects were also tested, along with serum muscle enzymes and manual muscle testing. RESULTS: Using immunoprecipitation, we identified 26 SRP(+) myositis patients and 77 SRP(-) controls (including 38 patients with necrotizing myopathy). Non-myositis control patients included SLE (n = 4) and SSc (n = 7) patients. Anti-SRP positivity by ELISA showed strong agreement (97.1%) with immunoprecipitation (κ = 0.94). The sensitivity, specificity, positive predictive value, and negative predictive value of the anti-SRP ELISA were 88, 100, 100 and 96, respectively. The area under the curve was 0.94, and test-retest reliability was strong (r = 0.91, P < 0.001). Serial samples showed that anti-SRP levels paralleled changes in muscle enzymes and manual muscle testing. CONCLUSION: We developed a quantitative ELISA for detecting serum anti-SRP autoantibodies and validated the assay in myositis. Longitudinal assessment of SRP levels by ELISA may be a useful biomarker for disease activity.

Biomarkers of rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVE: Interstitial lung disease (ILD) is a relatively common extraarticular manifestation of rheumatoid arthritis (RA) that contributes significantly to disease burden and excess mortality. The purpose of this study was to identify peripheral blood markers of RA-associated ILD that can facilitate earlier diagnosis and provide insight regarding the pathogenesis of this potentially devastating disease complication. METHODS: Patients with RA who were enrolled in a well-characterized Chinese identification cohort or a US replication cohort were subclassified as having RA-no ILD, RA-mild ILD, or RA-advanced ILD, based on high-resolution computed tomography scans of the chest. Multiplex enzyme-linked immunosorbent assays (ELISAs) and Luminex xMAP technology were used to assess 36 cytokines/chemokines, matrix metalloproteinases (MMPs), and acute-phase proteins in the identification cohort. Unadjusted and adjusted logistic regression models were used to quantify the strength of association between RA-ILD and biomarkers of interest. RESULTS: MMP-7 and interferon-γ-inducible protein 10 (IP-10)/CXCL10 were identified by multiplex ELISA as potential biomarkers for RA-ILD in 133 RA patients comprising the Chinese identification cohort (50 RA-no ILD, 41 RA-ILD, 42 RA-indeterminate ILD). The findings were confirmed by standard solid-phase sandwich ELISA in the Chinese identification cohort as well as an independent cohort of US patients with RA and different stages of ILD (22 RA-no ILD, 49 RA-ILD, 15 RA-indeterminate ILD), with statistically significant associations in both unadjusted and adjusted logistic regression analyses. CONCLUSION: Levels of MMP-7 and IP-10/CXCL10 are elevated in the serum of RA patients with ILD, whether mild or advanced, supporting their value as pathogenically relevant biomarkers that can contribute to noninvasive detection of this extraarticular disease complication.

Anti-transcription intermediary factor 1-gamma autoantibody ELISA development and validation.

OBJECTIVES: A quantitative anti-transcription intermediary factor 1-gamma (anti-TIF1-γ) ELISA may improve the detection of cancer-associated myositis (CAM). The aims of this study were the development and validation of a quantitative anti-TIF1-γ autoantibody ELISA in patients with myositis. METHODS: We developed an ELISA using recombinant purified full-length human TIF1-γ. Patient serum was incubated with TIF1-γ-coated ELISA plates, and secondary antibody that bound human IgG was used to detect anti-TIF1-γ binding. Protein immunoprecipitation (IP) was used as the gold standard for the presence of anti-TIF1-γ. Serum samples from myositis patients with positive and negative anti-TIF1-γ by IP, from non-myositis autoimmune patients (SSc, SLE and RA) and from healthy controls were analysed. The ELISA's sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were evaluated. Agreement between the ELISA and IP results was determined using chi-squared and kappa tests. Test-retest reliability of the ELISA was assessed. RESULTS: We identified 55 myositis patients with and 111 controls without anti-TIF1-γ by IP. Anti-TIF1-γ positivity by ELISA showed strong agreement (93.9%) with IP results (κ = 0.87). The sensitivity, specificity, PPV, NPV and overall accuracy of the anti-TIF1-γ ELISA were 91%, 96%, 93%, 95% and 94%, respectively. The area under the curve (AUC) of a receiver operating characteristic (ROC) curve was 0.938. Test-retest reliability was strong (Pearson r = 0.913, P < 0.001). CONCLUSION: We developed a quantitative ELISA for detecting serum anti-TIF1-γ autoantibodies and validated the assay in myositis and other connective tissue disease patients. The availability of a validated, quantitative ELISA should improve the detection of anti-TIF1-γ autoantibodies and may improve the detection of CAM.

Patients with non-Jo-1 anti-tRNA-synthetase autoantibodies have worse survival than Jo-1 positive patients.

OBJECTIVE: To compare the cumulative survival and event free survival in patients with Jo-1 versus non-Jo-1 anti-tRNA synthetase autoantibodies (anti-synAb). METHODS: Anti-synAb positive patients initially evaluated from 1985 to 2009 were included regardless of the connective tissue disease (CTD) diagnosis. Clinical data were extracted from a prospectively collected database and chart review. Survival between Jo-1 and non-Jo-1 was compared by log rank and Cox proportional hazards methods. RESULTS: 202 patients possessed anti-synAb: 122 Jo-1 and 80 non-Jo-1 (35 PL-12; 25 PL-7; 9 EJ; 6 KS; 5 OJ). The diagnoses at first visit for Jo-1 and non-Jo-1 patients were myositis in 83% and 40.0%, overlap or undifferentiated CTD in 17% and 47.5%, and systemic sclerosis in 0% and 12.5%, respectively (p<0.001). The median delay in diagnosis was 0.4 years in Jo-1 patients versus 1.0 year in non-Jo-1 patients (p<0.001). The most common causes of death in the overall cohort were pulmonary fibrosis in 49% and pulmonary hypertension in 11%. The 5- and 10-year unadjusted cumulative survival was 90% and 70% for Jo-1 patients, and 75% and 47% for non-Jo-1 patients (p<0.005). The hazard ratio (HR) of non-Jo-1 patients compared with Jo-1 patients was 1.9 (p=0.01) for cumulative and 1.9 (p=0.008) for event free survival from diagnosis. Age at first diagnosis and diagnosis delay but not gender, ethnicity and CTD diagnosis influenced survival. CONCLUSIONS: Non-Jo-1 anti-synAb positive patients have decreased survival compared with Jo-1 patients. The difference in survival may be partly attributable to a delay in diagnosis in the non-Jo-1 patients.

Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: a randomized, placebo-phase trial.

OBJECTIVE: To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients. METHODS: Adults with refractory polymyositis (PM) and adults and children with refractory dermatomyositis (DM) were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal values on core set measures (CSMs) for adults. Juvenile DM patients required ≥3 abnormal CSMs, with or without muscle weakness. Patients were randomized to receive either rituximab early or rituximab late, and glucocorticoid or immunosuppressive therapy was allowed at study entry. The primary end point compared the time to achieve the International Myositis Assessment and Clinical Studies Group preliminary definition of improvement (DOI) between the 2 groups. The secondary end points were the time to achieve ≥20% improvement in muscle strength and the proportions of patients in the early and late rituximab groups achieving the DOI at week 8. RESULTS: Among 200 randomized patients (76 with PM, 76 with DM, and 48 with juvenile DM), 195 showed no difference in the time to achieving the DOI between the rituximab late (n = 102) and rituximab early (n = 93) groups (P = 0.74 by log rank test), with a median time to achieving a DOI of 20.2 weeks and 20.0 weeks, respectively. The secondary end points also did not significantly differ between the 2 treatment groups. However, 161 (83%) of the randomized patients met the DOI, and individual CSMs improved in both groups throughout the 44-week trial. CONCLUSION: Although there were no significant differences in the 2 treatment arms for the primary and secondary end points, 83% of adult and juvenile myositis patients with refractory disease met the DOI. The role of B cell-depleting therapies in myositis warrants further study, with consideration for a different trial design.