Myositis Update: Treatment, Autoantibodies and More

Myositis Update: Treatment, Autoantibodies and More
Rare Disease Visiting Professor Grand Rounds Neurology/Neurosurgery University of Kansas Medical Center August 23, 2013 Chester V. Oddis, MD Division of Rheumatology and Clinical Immunology University of Pittsburgh

Questcor: Advisory Board
Disclosures Questcor: Advisory Board

Lecture Objectives Discuss general myositis classification and autoantibodies Discuss autoimmune ILD in myositis syndromes Review selected treatments and discuss newer potential therapeutic options for myositis Essentially none of the agents discussed today are “approved” for use in myositis

Conventional Classification of Myositis
Adult polymyositis (PM) Adult dermatomyositis (DM) Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another autoimmune disease Inclusion body myositis (IBM) To begin, we’d like to be able to classify or subset our patients with myositis and this old classification works ok.

If any of these pts comes to you with muscle weakness, the diagnosis is easy.

Gottron Papules

Rashes of Dermatomyositis
Gottron Sign

Heliotrope Rash

Facial Rash

Conventional Classification of Myositis
Adult polymyositis (PM) Adult dermatomyositis (DM) Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another autoimmune disease Inclusion body myositis (IBM) But what if there is no rash and the CK is elevated and the pt is weak?

Polymyositis Mimics Endocrine myopathies Drug or toxic myopathies
hyper/hypothyroid Drug or toxic myopathies Metabolic myopathies Mitochondrial myopathies Muscular dystrophies Infectious myositis Neuropathies/neurologic syndromes Paraneoplastic syndromes Other connective tissue disorders Miscellaneous amyloid, sarcoid

Elevated Muscle Enzymes in the Absence of Muscle Disease
Demographics BM > BF > WM > WF Racial variation in serum CK Healthy asymptomatic blacks have higher serum CK levels than whites or Hispanics Exercise/Manual Labor Idiopathic HyperCKemia Johnston et al, JRSM, 1996 Prelle et al, J Neurol, 2002

We can classify pathologically

IBM DM PM NM Histopathologic findings in Inflammatory Myopathy:
Dermatomyositis. Perifascicular atrophy is outlined by the arrows along with perimysial (p) mononuclear cell inflammation (H&E). Inclusion body myositis. Atrophic and hypertrophic fibers are seen along with an increase in endomysial connective tissue. A myofiber is surrounded and being invaded by lymphocytes (long arrow) while another contains multiple rimmed vacuoles (short arrow) (Gomori trichrome, cryostat section). Polymyositis. A myofiber (arrow) is surrounded by inflammatory cells and reactive to major histocompability complex type 1 (MHC 1 immunostain, cryostat section) Autoimmune necrotizing myopathy. This specimen is from a patient with SRP Ab. There is an acutely necrotic myofiber (arrow) and an atrophic regenerating fiber in this field. Lymphocytes were absent. (H&E) But….these are great, selected pictures. But not everyone gets biopsied and there is considerable sampling error so you have to sometimes be lucky to get the answer on biopsy.

IIM Serologic Classification
“Myositis-specific” (MSA) ARS (anti-synthetase) Mi-2 CADM 140 (MDA-5) SAE MJ P155/140 (TIF1-γ) SRP HMG CoA reductase (statin NM) Myositis-associated (MAA) anti-PM/Scl, Ku, U1/U2/U3RNP MSA/MAA negative Although many of us were trained to look at the myositis subsets clinically and we still often describe them this way, it makes more sense, in many ways, to look at these pts in terms of the autoAb subsets.

Myositis Autoantibody Subsets
Anti-Synthetases PL-7 PL-12 EJ Mi-2 Jo-1 TIF-1γ SAE PM/NM MDA-5 SRP MJ PM-Scl This is a diagrammatic representation of the autoAbs known to be associated with myositis utilizing a breakdown by clinical myositis subset. This may be helpful but you don’t really get any clinical feel for what the autoAb is associated with and you don’t learn anything about the autoantigenic target. HMGCR DM Overlap U1RNP Ku

Classification of Myositis
Adult polymyositis Adult dermatomyositis Amyopathic DM (ADM) Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another autoimmune disease Inclusion body myositis (IBM) Necrotizing myopathy Statin/anti-SRP We can also make the list a bit more complicated and expand the classification clinically (ADM) and pathologically (NM) to make the list longer and more complete

Clinically Amyopathic DM (CADM)
A subset of DM patients with cutaneous manifestations of DM for 6 months or longer No proximal muscle weakness May have elevated serum muscle enzymes, mild EMG abnormalities/biopsy findings CADM = Amyopathic DM (ADM) + Hypomyopathic DM (HDM)

Malignancy and CADM Frequency of malignancy probably similar in CADM and classic DM 41/291 (14%) in ADM review series (Gerami, 2006) 15% in classic DM (Sigurgeirsson, NEJM, 1992) Antibody positivity may not be “protective”

CADM and Lung Disease 19/197 (10%) ADM pts had ILD Challenge
review of literature Challenge They may be missed if the rash of DM is missed Gerami, J Am Acad Dermatol, 2006

PL-7 PL-12 EJ Mi-2 Jo-1 TIF-1γ SAE ADM PM/NM MDA-5 SRP MJ PM-Scl HMGCR DM Overlap U1RNP Ku

Supports role of a viral trigger
Anti-CADM-140 Amyopathic DM with rapidly progressive ILD in Japanese (Sato, Arth Rheum, 2005 and 2009) Acute/subacute interstitial pneumonitis in DM in Chinese (Chen, Rheum Int, 2011) Also described in other Asian populations with similar phenotype Target autoantigen is MDA-5. What is MDA-5? Involved in innate immune defense against viruses Supports role of a viral trigger

Anti-CADM-140 Novel cutaneous phenotype of palmar papules and cutaneous ulcerations – severe vasculopathy Rapidly progressive ILD Fiorentino, J Am Acad Derm, 2011

Case One 70 year old WM “Double pneumonia” in 6/2012
Rash of DM in 9/2012 Vasculitic skin changes in 1/2013 No muscle weakness Cytoxan for ILD

Case Two Pt referred for “Amyopathic DM”
44 yo WF with mild Gottron’s rash and periungual changes Normal muscle enzymes (LDH 256) Subtle iliopsoas weakness at 4+/5 “Borderline” myopathic changes in deltoid

Percutaneous needle muscle biopsy

Case Two: Teaching Points
Careful physical examination is important no subjective symptoms, nl CK, essentially nl EMG Normal-CK, active myositis occurs! particularly dermatomyositis (juvenile and adult) other enzymes may also be normal Muscle biopsy still helpful

Case Three 41 y.o. white male with HTN, dyslipidemia
3/20: periorbital edema 3/27: acute polyarthritis 4/7: dyspnea, fever 4/11: admitted to outside hospital with bilateral pulmonary infiltrates 4/26: worsening dyspnea; unresponsive to antibiotics and steroids and transferred to UPMC 4/27: Post bronchoscopy and BAL/biopsy; dyspneic male with no history of muscle or lung problems; O2 saturation 90% (100% O2 mask/nasal cannula) ROS: no Raynauds, mild joint pain Exam: drug rash but no heliotrope or Gottron’s sign; diffuse rales; no synovitis; normal muscle strength Labs: CK 657; ANA negative; other labs essentially normal

Anti-synthetase Syndrome
Defines a clinically homogeneous patient population Fever Myositis Arthritis (misdx as RA) Raynaud phenomenon Mechanic’s hands ILD The presence of an anti-syn Ab often leads to the finding of several unifying clinical features termed the “the anti-synth. syndrome.”

Anti-synthetases PL-7 PL-12 EJ Mi-2 Jo-1 TIF-1γ SAE PM/NM MDA-5 SRP MJ PM-Scl Back to our autoAb diagram I want to finish with the largest (and arguably the most interesting) subset of autoAbs associated with myositis – the antisynthetase subset. HMGCR DM Overlap U1RNP Ku

Anti-synthetase Autoantibodies

Myositis-Associated ILD
30-40% IIM patients have ILD most commonly involved extramuscular organ Significant contribution to morbidity/mortality Strong association of ILD with all anti-synthetase autoAbs

Making the Diagnosis of Autoimmune ILD?
Not everyone will present with the classic anti-synthetase syndrome We’re not going to miss the classic anti-synthetase patient like I presented … but we might miss the subtle cases

Recognize ‘incomplete’ clinical syndromes ILD alone or ILD with subtle CTD findings We’re not going to miss the classic anti-synthetase patient like I presented … but we might miss the subtle cases

University of Pittsburgh Anti-synthetase Cohort
Autoantibody Number (% synthetases) Jo-1 140 (60%) PL-12 36 (16%) PL-7 27 (12%) EJ 11 (5) OJ 6 (3) KS 9 (4) Total Synthetases 229 Although many consider these autoAbs to be rare they are not that uncommon. Realizing we are a tertiary care center we may see more than our share but this gives you an idea over about 20 years.

Other Anti-synthetases
Initial CTD Symptom in Anti-syn Cohort * p<0.02 I realize this slide is busy but I have broken down the Jo-1 and non-Jo-1 subset in our Pittsburgh cohort. This slide summarizes the 1st symptom pts report and the important thing to note is that although these are considered MSAs the symptoms are quite diverse – especially when you consider the non-Jo-1 pts. Just looking at the highlighted comparison of Raynauds, joint and muscle features, one sees Raynaud more common in the non-Jo-1 subset while myositis and arthritis symptoms are less frequent. Thus, more UCTD – like. Jo-1 (n=122) Other Anti-synthetases (n=80) - Raynaud’s more common as initial symptom in non-Jo-1 subset - Muscle and joint less frequent initial symptom in non-Jo-1 subset Aggarwal, Ann RD, 2013

Jo-1 vs. Other Synthetases: Clinical Presentation
Mean Age at Symptom Onset (yrs) % Female % Caucasian Diagnoses at First Visit (%) Median Delay in Dx from 1st CTD Symptom (years; IQR) Myositis Overlap or UCTD SSc Jo-1 (n=122) 45 67 86 83 17 0.4 ( ) non-Jo-1 (n=80) 46 70 79 40 48 13 1.0 ( ) p value NS p<0.001 In 60% of cases, non-Jo-1 pts did NOT have a myositis Dx at their initial visit Non-Jo-1 patients had a longer delay in Dx than Jo-1 patients Aggarwal, Ann RD, 2013

Cause of Death in Anti-synthetase Cohort
- In synthetase (+) pts pulmonary disease was most common cause of death Aggarwal, Ann RD, 2013

Pulmonary Cause of Death
Jo-1 vs. Other Anti-synthetases: Outcome Pulmonary Cause of Death Cumulative Survival % Median Survival (yrs) Fibrosis PAH 5 year 10 year Jo-1 (n=122) 16/36 3/36 90 70 15 non-Jo-1 (n=80) 16/30 4/30 75 47 9 p value NS p<0.005 p<0.01 Pulmonary cause of death was similar between groups Non-Jo-1 pts had decreased survival compared to Jo-1 pts Aggarwal, Ann RD, 2013

Recognize ‘incomplete’ clinical syndromes ILD alone or ILD with subtle CTD findings ‘Myositis-specific Abs’ in the absence of myositis We’re not going to miss the classic anti-synthetase patient like I presented … but we might miss the subtle cases

Recognize ‘incomplete’ clinical syndromes ILD alone or ILD with subtle CTD findings ‘Myositis-specific Abs’ in the absence of myositis Negative ANA We’re not going to miss the classic anti-synthetase patient like I presented … but we might miss the subtle cases

Case Three 41 y.o. white male with HTN, dyslipidemia
3/20: periorbital edema 3/27: acute polyarthritis 4/7: dyspnea, fever 4/11: admitted to outside hospital with bilateral pulmonary infiltrates 4/26: worsening dyspnea; unresponsive to antibiotics and steroids and transferred to UPMC 4/27: Post bronchoscopy and BAL/biopsy; dyspneic male with no history of muscle or lung problems; O2 saturation 90% (100% O2 mask/nasal cannula) ROS: no Raynauds, mild joint pain Exam: drug rash but no heliotrope or Gottron’s sign; diffuse rales; no synovitis; normal muscle strength Labs: CK 657; ANA negative; other labs essentially normal

Anti-Jo-1 Autoantibody
Directed against histidyl-tRNA synthetase Ag: enzyme that catalyzes binding of an amino acid to its tRNA in process of protein synthesis histidine his tRNA syn Ag tRNA for histidine

A Negative ANA Does Not Imply Antibody Negativity
Homogeneous, diffuse cytoplasmic staining Dimitri, Muscle and Nerve, 2007

ANA + Anti-CytAb + p value Anti-Syn patients
Frequency of ANA and Cytoplasmic Staining in Anti-synthetase Patients ANA + Anti-CytAb + p value Anti-Syn patients 100/199 (50%) 142/196 (72%) p < 0.001 Aggarwal, ACR 2010

ANA + Anti-CytAb + p value Anti-Syn patients
Frequency of ANA and Cytoplasmic Staining in Anti-synthetase Patients ANA + Anti-CytAb + p value Anti-Syn patients 100/199 (50%) 142/196 (72%) p < 0.001 All Jo-1 62/119 (52%) 77/116 (66%) p = 0.026 All non-Jo-1 38/80 (48%) 65/80 (81%) Aggarwal, ACR 2010

ANA + Anti-CytAb + p value Anti-Syn patients SSc
Frequency of ANA and Cytoplasmic Staining in Anti-synthetase Patients ANA + Anti-CytAb + p value Anti-Syn patients 100/199 (50%) 142/196 (72%) p < 0.001 All Jo-1 62/119 (52%) 77/116 (66%) p = 0.026 All non-Jo-1 38/80 (48%) 65/80 (81%) SSc 1935/1946 (99%) 180/1946 (9%) Aggarwal, ACR 2010

How Can You Miss Autoimmune ILD?
Failure to recognize ‘incomplete’ clinical syndromes ‘Myositis-specific Abs’ in the absence of myositis aren’t ordered or not detected Reassured by the negative ANA So I asked a different question in this slide but answer it with the 3 things we just discussed.

Myositis Autoantibodies
Antibody Target Subset Phenotype CADM-140 MDA-5 DM Amyopathic, ILD Jo-1 Other anti-Syn ARS PM/DM Anti-synthetase syndrome Mi-2 NuRD Shawl, V-neck, Gottron’s This table summarizes some of the features of the autoAbs seen with myositis. To do justice to the clinical features of these autoAbs just in this table alone is a lecture in itself. So I want to use about 1 slide/autoAb on most of them – not even all of them.

Severe/refractory necrotizing myositis
Myositis Autoantibodies Antibody Target Subset Phenotype CADM-140 MDA-5 DM Amyopathic, ILD Jo-1 Other anti-Syn ARS PM/DM Anti-synthetase syndrome Mi-2 NuRD Shawl, V-neck, Gottron’s SAE SUMO ILD, dysphagia MJ NXP-2 JDM Calcinosis, ulceration p155/140 TIF1-g DM, JDM Severe skin, malignancy SRP Signal recognition particle 72, 54 kDa PM Severe/refractory necrotizing myositis 200/100 kD HMGCR IMNM Necrotizing myopathy This table summarizes some of the features of the autoAbs seen with myositis. To do justice to the clinical features of these autoAbs just in this table alone is a lecture in itself. So I want to use about 1 slide/autoAb on most of them – not even all of them.

Myositis Treatment: Beyond Steroids, Methotrexate and Azathioprine

Pharmacologic Therapy of IIM
Corticosteroids Immunosuppressive Agents Combination regimens IVIg Biologic agents

Corticosteroids in Myositis
Empirically remain initial treatment of choice Begin divided dose prednisone at 60 mg daily (30 mg bid) Continue until serum CK falls to normal Consolidate to single morning dose Taper by 25% existing dose q 3-4 weeks to 5-10 mg daily maintenance dose Continue until active disease suppressed one year Improvement in strength lags behind CK improvement

This is a review we published about 1 year ago on Tx – couple points to be made: (1) print is too small to learn anything and (2) note the level of evidence we’re dealing with. Aggarwal/Oddis, Curr Rheum Rep, 2011

Combination Therapy in Myositis
Multiple reports of combination therapy in treatment of refractory PM and DM Literature support for combination of methotrexate and azathioprine in IIM [Villalba, Arthritis Rheum, 1998] effective in treatment-resistant myositis beneficial in those who had failed either mtx or aza alone

IS Agents Beyond Mtx and Aza…
Mycophenolate mofetil

Mycophenolate Mofetil in Myositis
6 of 10 patients with DM successfully tapered CS with MMF [Rowin, Neurology, 2006] 3 developed opportunistic infections (other risk factors) Improvement in cutaneous features in 10/12 DM patients [Edge, Arch Derm, 2006] IVIg as add-on therapy to MMF effective in 7 severe and refractory pts (4PM/3DM) [Danielli, Autoimmunity Rev, 2009] Safe and steroid-sparing Retrospective review of 50 JDM pts using MMF for 12 months [Rouster-Stevens, Arth Care Rsch, 2010] Improved skin and muscle and steroid-sparing; well-tolerated

IS Agents Beyond Mtx and Aza…
Mycophenolate mofetil Cyclosporine/tacrolimus Cyclophosphamide

Treatment of ILD in Myositis Patients
Corticosteroids remain the initial treatment Cyclophosphamide and azathioprine used early or in CS resistant cases with variable results Intermittent IV ctx pulse [Okada, Mod Rheumatol, 2007] MMF in CTD-associated ILD [Swigris, Chest, 2006; Fischer, J Rheum, 2013] Cyclosporine and tacrolimus used in both adult and pediatric patients with promising results

Tacrolimus in Myositis and ILD
Parameter p-value FVC <0.0001 FEV-1 DLCO 0.0046 CK MMT 0.06 CS Dose Retrospective study of 13 synthetase (+) pts (12 with Jo-1) Wilkes, Arth Rheum, 2005

Is Anti-T cell Therapy Rational in Myositis-associated ILD?
65

T cells as Therapeutic Targets in Myositis- Associated ILD
Pathology: abundant lymphocytes and plasma cells in the lung of PM/DM pts (form lymphoid follicles) Infiltrating lymphocytes in myositis NSIP pts revealed “activated” CD8+ T-cells [Yamadori, Rheumatol Int, 2001] CD8+ and “activated” T-cells increased in BAL fluid of PM/DM pts (n=22) [Kurasawa, Clin Exp Immunol, 2002] Decrease in regulatory T cells in IP of CTD-ILD [Katigiri, Mod Rheumatol, 2008] Implicates activated CD8+ T-cells in myositis-associated ILD 66

Anti-T cell Therapy in Myositis-associated ILD
Accumulating data on efficacy of tacrolimus/CsA Wilkes, Arth Rheum, 2005 Takada, Autoimmunity, 2005 Takada, Mod Rheumatol, 2007 Guglielmo, Eur Respir J, 2009 ARDS reversed with tacrolimus Ando, Clin Rheumatol, 2010 ADM pt refractory to CsA responded to tacrolimus A Abatacept should also be studied in AILD

IVIg in Myositis Randomized, double-blind, placebo- controlled study of 15 treatment-resistant DM patients demonstrated efficacy [Dalakas, NEJM, 1993] No significant side effects; felt to be safe and effective for refractory DM

IVIg in Myositis Literature review of 308 adult patients
14 articles only 2 RCT Safe with tolerable adverse events Steroid-sparing in setting of infection Effective in esophageal involvement “Acute” complications or rapidly progressive disease Effective for refractory rash Wang, Clin Rheumatol, 2012

Biologic Targets TNF – alpha

Anti-TNF-α Therapy in Myositis
TNF-α and other proinflammatory cytokines are increased in muscle tissue of myositis patients [Lundberg, RDCNA, 2002] TNF-α is toxic to myofibers and prevents their regeneration TNF-α enhances other inflammatory cytokines in DM and PM

A Randomized, Pilot Study of Etanercept in Dermatomyositis
Anthony A. Amato, M.D. Brigham and Women’s Hospital Harvard Medical School & THE MUSCLE STUDY GROUP Amato, Ann Neurol, 2011

Biologic Targets TNF – alpha B cell

Rituximab in Myositis Open label study uncontrolled pilot trial in 7 adult refractory DM pts Levine, Arth Rheum, 2005 Effective in antisynthetase syndrome Brulhart, Ann Rheum Dis, 2006 Sem, Rheumatol, 2009 Effective in refractory myositis and DM rash (some longstanding remission) Mok, J Rheumatol, 2007 Dinh, J Am Acad Derm, 2007 Ineffective for DM rash Chung, Arch Dermatol, 2007

Rituximab in Myositis Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis Chester V. Oddis, MD Ann M. Reed, MD and the RIM Study Group

Participating Centers
Adult Sites Alabama (Fessler) Boston (Narayanaswami) Cedars Sinai (Venuturupalli/Weisman) Czech Republic (Vencovsky) Dallas (Olsen) Kansas City (Barohn/Latinis) Kentucky (Crofford) London (Isenberg) Mayo Clinic (Ytterberg) Miami (Sharma) Michigan (Seibold/Schiopu) Michigan State (Martin/Eggebeen) Milwaukee (Cronin) New York: North Shore (Marder) New York: HSS (DiMartino) NIH (Miller) Philadelphia (Kolasinski) Phoenix (Levine) Pittsburgh (Oddis/Ascherman) Stanford (Chung/Fiorentino) Sweden (Lundberg) Pediatric Sites Boston (Kim) Cincinnati (Lovell) Duke (Rabinovich) Mayo Clinic (Reed) Miami (Rivas-Chacon) Michigan State (Martin/Eggebeen) NIH (Rider) Nova Scotia (Huber) Philadelphia (Sherry) Pittsburgh (Kietz) Stanford (Sandborg) Toronto (Feldman) Made changes: Michigan should be changed to Seibold and Schiopu The 2 adult New York sites should be distinguished from each other – i.e. location ; Marder-North Shore; DiMartino: HSS Stanford is spelled wrong and should be Chung and Fiorentino UCLA should be Weisman and Venuturupalli 78

RIM Trial Summary Primary and secondary endpoints were not achieved
83% of refractory adult and juvenile myositis patients met the Definition of Improvement in this trial There was a significant corticosteroid sparing effect noted in this trial between the baseline dose and the dose at study conclusion Rituximab was generally well tolerated

Biologic Targets TNF – alpha B cell Other Interleukin – 6 Type 1 IFN

IL-6 Blockade in Murine Model of PM
IL-6 critically involved in development of myositis and muscles expressed IL-6 Treatment with tocilizumab was effective in amelioration of myositis IL-6 blockade is potential new approach to treatment of myositis Anti-IL-6 effective/approved for RA Okiyama, Arth Rheum, 2009

Microarrays of DM and Normal Muscle
Cluster of genes known to be induced by IFN-α/β DM: genes were highly over-expressed compared to controls Greenberg, Ann Neurol, 2005 Gene expression: Red: high; black: intermed; green: low

Type I IFN Gene Expression in DM
DM patients Type I IFN Gene Expression in DM Results essentially duplicated with blood IFN signature correlating with disease activity Also, multiplex ELISAs demonstrate increased levels of IFN-regulated chemokines that also correlated with disease activity IP-10, MCP-1, MCP-2 IFN signature, IFN-related cytokines both correlated with disease activity Baechler, Mol Med, 2007

Type I IFN Genes, Chemokines and IL-6 in DM
Blood IFN gene expression, ELISA-based IFN-regulated chemokines and IL-6 in adult DM and JDM (n=56 pts) Peripheral blood samples and clinical data were obtained from 56 patients with adult or juvenile DM. The type I IFN gene signature in the whole blood of patients with DM was defined by determining the expression levels of 3 IFN-regulated genes (IFIT1, G1P2, and IRF7) using quantitative real-time reverse transcription–polymerase chain reaction. Multiplexed immunoassays were used to quantify the serum levels of 4 type I IFN–regulated chemokines (IFN-inducible T cell chemoattractant, IFN-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], and MCP-2) and the serum levels of other proinflammatory cytokines, including interleukin-6 (IL-6). DM disease activity correlated significantly with the type I IFN gene signature and with the type I IFN chemokine signature. Furthermore, the serum levels of IL-6 were significantly correlated with disease activity . In addition, correlations between the serum levels of IL-6 and both the type I IFN gene signature and the type I IFN chemokine signature were detected in patients with DM. Conclusion. These results suggest that serum IL-6 production and the type I IFN gene signature are candidate biomarkers for disease activity in adult and juvenile DM. Coregulation of the expression of IFN-driven chemokines and IL-6 suggests a novel pathogenic linkage in DM. Bilgic, Arth Rheum, 2009

Blood IFN gene expression, ELISA-based IFN-regulated chemokines and IL-6 in adult DM and JDM (n=56 pts) Elevated levels of IL-6 and type I IFN–regulated transcripts and proteins in blood of adult DM and JDM Peripheral blood samples and clinical data were obtained from 56 patients with adult or juvenile DM. The type I IFN gene signature in the whole blood of patients with DM was defined by determining the expression levels of 3 IFN-regulated genes (IFIT1, G1P2, and IRF7) using quantitative real-time reverse transcription–polymerase chain reaction. Multiplexed immunoassays were used to quantify the serum levels of 4 type I IFN–regulated chemokines (IFN-inducible T cell chemoattractant, IFN-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], and MCP-2) and the serum levels of other proinflammatory cytokines, including interleukin-6 (IL-6). DM disease activity correlated significantly with the type I IFN gene signature and with the type I IFN chemokine signature. Furthermore, the serum levels of IL-6 were significantly correlated with disease activity . In addition, correlations between the serum levels of IL-6 and both the type I IFN gene signature and the type I IFN chemokine signature were detected in patients with DM. Conclusion. These results suggest that serum IL-6 production and the type I IFN gene signature are candidate biomarkers for disease activity in adult and juvenile DM. Coregulation of the expression of IFN-driven chemokines and IL-6 suggests a novel pathogenic linkage in DM. Bilgic, Arth Rheum, 2009

Blood IFN gene expression, ELISA-based IFN-regulated chemokines and IL-6 in adult DM and JDM (n=56 pts) Elevated levels of IL-6 and type I IFN–regulated transcripts and proteins in blood of adult DM and JDM IFN gene/protein signatures and serum IL-6 levels correlated with DM disease activity and with each other Peripheral blood samples and clinical data were obtained from 56 patients with adult or juvenile DM. The type I IFN gene signature in the whole blood of patients with DM was defined by determining the expression levels of 3 IFN-regulated genes (IFIT1, G1P2, and IRF7) using quantitative real-time reverse transcription–polymerase chain reaction. Multiplexed immunoassays were used to quantify the serum levels of 4 type I IFN–regulated chemokines (IFN-inducible T cell chemoattractant, IFN-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], and MCP-2) and the serum levels of other proinflammatory cytokines, including interleukin-6 (IL-6). DM disease activity correlated significantly with the type I IFN gene signature and with the type I IFN chemokine signature. Furthermore, the serum levels of IL-6 were significantly correlated with disease activity . In addition, correlations between the serum levels of IL-6 and both the type I IFN gene signature and the type I IFN chemokine signature were detected in patients with DM. Conclusion. These results suggest that serum IL-6 production and the type I IFN gene signature are candidate biomarkers for disease activity in adult and juvenile DM. Coregulation of the expression of IFN-driven chemokines and IL-6 suggests a novel pathogenic linkage in DM. Bilgic, Arth Rheum, 2009

Blood IFN gene expression, ELISA-based IFN-regulated chemokines and IL-6 in adult DM and JDM (n=56 pts) Elevated levels of IL-6 and type I IFN–regulated transcripts and proteins in blood of adult DM and JDM IFN gene/protein signatures and serum IL-6 levels correlated with DM disease activity and with each other Suggests that coordinated dysregulation of type I IFN signaling and IL-6 production may contribute to DM pathogenesis Peripheral blood samples and clinical data were obtained from 56 patients with adult or juvenile DM. The type I IFN gene signature in the whole blood of patients with DM was defined by determining the expression levels of 3 IFN-regulated genes (IFIT1, G1P2, and IRF7) using quantitative real-time reverse transcription–polymerase chain reaction. Multiplexed immunoassays were used to quantify the serum levels of 4 type I IFN–regulated chemokines (IFN-inducible T cell chemoattractant, IFN-inducible 10-kd protein, monocyte chemotactic protein 1 [MCP-1], and MCP-2) and the serum levels of other proinflammatory cytokines, including interleukin-6 (IL-6). DM disease activity correlated significantly with the type I IFN gene signature and with the type I IFN chemokine signature. Furthermore, the serum levels of IL-6 were significantly correlated with disease activity . In addition, correlations between the serum levels of IL-6 and both the type I IFN gene signature and the type I IFN chemokine signature were detected in patients with DM. Conclusion. These results suggest that serum IL-6 production and the type I IFN gene signature are candidate biomarkers for disease activity in adult and juvenile DM. Coregulation of the expression of IFN-driven chemokines and IL-6 suggests a novel pathogenic linkage in DM. Bilgic, Arth Rheum, 2009

Summary Myositis is heterogeneous and autoAbs help in classification and treatment Lung disease is a critical prognostic determinant Exciting time for therapeutic intervention in myositis Temper our enthusiasm with a respect for all of these novel agents and their short and long- term side effects

RIM Study: Trial Design
“Randomized Placebo Phase” Wks 0/1 Wks 8/9 Weeks 12 – 44 Monthly Assessments Screen Rituximab Placebo Rtx Early Rtx Late Placebo Rituximab 200 myositis patients: 76 adult polymyositis (PM), 76 adult dermatomyositis (DM) and 48 Juvenile dermatomyositis (JDM) patients Subjects randomly assigned, double-blind, to ‘Rtx Early’ or ‘Rtx Late’ Patients were followed for 44 weeks Myositis Core Set Measures (CSM) were assessed monthly Oddis, Arthritis Rheum, 2013

Primary Endpoint and Hypothesis
Primary Endpoint: Compare the time to DOI between the ‘Rtx Early’ and ‘Rtx Late’ groups Hypothesis: The time to DOI will be statistically less (shorter) in early vs. late treatment groups

B cell Numbers Before and After Rituximab
Early Rtx Late Rtx

Primary Outcome: Entire Cohort
Median time to DOI: Early Rtx = 20.0 weeks Late Rtx = 20.2 weeks p = 0.74 (log rank)

Primary Outcome: JDM Median time to DOI: Early Rtx = 11.7 weeks
Late Rtx = 19.6 weeks p = 0.32 (log rank)

Patients Meeting DOI During Trial
Early Rtx Late Rtx 85% 80% Overall, 83% (161/195) of subjects met the DOI during the course of the 44-week clinical trial 95

Corticosteroid Sparing Effect
There was a significant difference in the mean corticosteroid dose at baseline compared to the final visit 96

Kaplan Meier: Myositis Autoantibody Subsets
MAA = myositis associated antibody Probability of Not Meeting DOI Myositis autoantibodies esp anti-Jo1 and anti-Mi-2 were strongly associated with improvement. This slide show Kaplan Meier curves of all the autoantibody groups. The lower curve represents a faster time to improvement. The primary and strongest predictor variable on univariate analysis was the autoantibody. Anti-Jo-1, in red, and anti-Mi-2, in black, were significantly better predictor of improvement than the “no autoantibody” group noted by the blue line.

Future Directions: Anti-Jo-1 as Biomarker
Jo-1 levels decreased after rituximab and strongly correlated with disease activity Rho = Median Rho = 0.68 The findings regarding anti-Jo-1 are even more interesting with this data that shows that anti-Jo-1 autoAb levels decreased after rituximab as shown in graph on left. And anti-Jo-1 levels longitudinally correlated with myositis activity as shown in graph on right. This may suggest that anti-Jo-1 is a disease biomarker. Abstract #750, ACR 2012

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