Myositis and Autoimmune ILD

Transcription

1 Myositis and Autoimmune ILD 2018 AURA Annual Meeting Sedona, Arizona June 2, 2018 Chester V. Oddis, MD Director, Myositis Center University of Pittsburgh

2 Disclosures Genentech: Clinical trial support Idera: Clinical trial participant Mallinckrodt: Clinical trial support; Advisory Board

3 Lecture Objectives Discuss selected clinical features of myositis classification. Discuss spectrum of autoantibodies seen in patients with myositis and their clinical associations Discuss selected treatment aspects of myositis and autoimmune ILD

4 Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM)

5 IIM: Diagnostic Criteria Bohan and Peter (1975) Symmetric proximal muscle weakness Elevation of serum muscle enzymes: CK, aldolase, AST, ALT, LDH Myopathic electromyographic abnormalities: sharp waves, fibrillations, polyphasic motor units, high frequency repetitive discharges Characteristic muscle pathology: myofiber degeneration/regeneration, MNC infiltrates, perifascicular atrophy

6 Rashes of Dermatomyositis Rashes of Dermatomyositis

7 Cuticular Thickening and Periungual Erythema Nail fold capillary abnormality

8 Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM)

9 Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM)

10 Polymyositis Mimics Endocrine 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

11 Muscle Biopsy is a Must in Polymyositis (unlike classic DM)

12 Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) What we called PM before, in some cases, is now called NM

13 Neurology, 2003

14 Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) What we called PM before, in some cases, is now called NM

15 Medicine, 2005

16 Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) What we called PM before, in some cases, is now called NM

17 Lundberg et al, Ann RD, 2018 For patients without classic DM rashes, do a muscle biopsy. For DM patients without muscle involvement do a skin biopsy. These criteria provide a score and probability for having IIM (for clinical trial purposes)

18 Case One 67 year old Caucasian female with HTN, hyperlipidemia, uterine cancer (1997) July, 2004: atorvastatin June, 2008: lower extremity weakness Spring, 2009: difficulty walking up steps and lifting arms overhead June, 2009: stops atorvastatin on her own but no improvement in weakness September, 2009: CK 6473, repeat 9375 Admitted to hospital; muscle biopsy: myonecrosis, no inflammation or vasculitis

19 Necrotizing Myopathy Kassardjian, JAMA Neurol, 2015

20 Case One 67 year old Caucasian female with HTN, hyperlipidemia, uterine cancer (1997) July, 2004: atorvastatin June, 2008: lower extremity weakness Spring, 2009: difficulty walking up steps and lifting arms overhead June, 2009: stops atorvastatin on her own but no improvement in weakness September, 2009: CK 6473, repeat 9375; ANA 1:320 (H) Admitted to hospital; muscle biopsy: myonecrosis, no inflammation or vasculitis Treated with prednisone (60mg/day) and CK and weakness improve

21 Case One March, 2010 (1 st UPMC visit) CK 5800 (increasing as prednisone tapered) No other autoimmune manifestations; no FH of autoimmune diseases No rashes of dermatomyositis Deltoids 4+/5; neck flexors 4/5; iliopsoas 3+/5 Statin myopathy Pt hesitant to increase prednisone

22 Immune-Mediated Necrotizing Myopathy Associated with Statins Proximal weakness during or after statin use Elevated CK Persistent weakness and elevated CK despite stopping the statin Improvement with IS agents Muscle biopsy showing necrotizing myopathy without significant inflammation Grable-Esposito, Muscle & Nerve, 2010

23 Anti-200/100 kd AutoAb Defines Subgroup of Necrotizing Myopathy (NM) 16/38 patient sera with NM had the doublet All were weak with high CK 63% had statin exposure prior to weakness 83% >age 50 exposed to statins All responded to IS therapy and many relapsed Controls in lanes 5 and 10 Christopher-Stine, Arth Rheum, 2010

24 Statin Necrotizing Myopathy HMGCR was identified as the 100-kd autoantigenic target Developed an ELISA for anti-hmgcr autoab All 16 doublet positive pts were anti-hmgcr (+) 45/750 (6%) of cohort were anti-hmgcr (+) Mammen, Arth Rheum, 2011

25 Case One April-June, 2010: worse weakness; CK 6367 July, 2010: prednisone increased (60mg/d) and mtx added Jan, 2011: added imuran/mtx (25mg/week), pred 30mg/d May, 2011: added IVIg; continued other IS agents August, 2011: clearly improved with first normal CK in July November, 2011: 5/5 strength; taper IVIg (never off completely) March, 2012: stopped imuran June, 2012: off prednisone Progressive rise of CK ; went back on mtx and IVIg; CK still elevated

26 Case One April-June, 2010: worse weakness; CK 6367 July, 2010: prednisone increased (60mg/d) and mtx added Jan, 2011: added imuran/mtx (25mg/week), pred 30mg/d May, 2011: added IVIg; continued other IS agents August, 2011: clearly improved with first normal CK in July November, 2011: 5/5 strength; taper IVIg (never off completely) March, 2012: stopped imuran June, 2012: off prednisone Progressive rise of CK ; went back on mtx and IVIg; CK still elevated Pt is anti-hmgcr autoab positive

27 Features of Anti-SRP Subset Acute onset of severe weakness with myalgias; high CK Necrotizing myopathy (or PM phenotype) no DM rash; ILD rare Poor response to therapy with variable prognosis Refractory, persistently high CK, dystrophy-like

28 Muscle Pathology of SRP Antibody Subset Necrotizing myopathy without inflammation Dimitri, Muscle and Nerve, 2007

29 Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) Anti-HMGCR Anti-SRP

30 Classification of Myositis Adult polymyositis Adult dermatomyositis Amyopathic Dermatomyositis Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) Anti-HMGCR Anti-SRP

31 Sometimes the skin disease can be the most dominant feature

32

33 DM Scalp Rash

34 Treatment of DM Cutaneous Disease Sun-protective measures; avoid photosensitive meds Topical GC (potency depends on severity) Topical calcineurin inhibitors (tacrolimus, pimecrolimus) Antimalarials (hydroxychloroquine or chloroquine); some dermatologists add quinacrine Oral glucocorticoids (varying doses) No Clinical Response after 1-3 months? Yes 2 nd Line Methotrexate (oral/sq) MMF 3 rd Line Taper prednisone by 20-25% monthly to minimum effective dose IVIG Tacrolimus Cyclophosphamide Rituximab

35 Apremilast in DM 50 yo woman failing GC, HCQ, aza, aza/mtx, MMF, IVIg, tacrolimus, dapsone and Acthar gel After 3 months

36 Tofacitinib in DM: Case 1 3 months 55 yo female Failed or partially responsive to GC, mtx, HCQ, aza, MMF, chloroquine, Acthar gel, tacrolimus, IVIg

37 Tofacitinib in DM: Case 2 67 yo woman with rash and arthritis Refractory to GC, mtx, HCQ, MMF, tacrolimus and Acthar gel Continued IVIg DM rash inactive (0/10) after 6 months

38 Tofacitinib in DM: Case 3 42 yo Caucasian male Rash and polyarthritis Previous mtx, MMF, HCQ, aza, intolerant to IVIg After 3 months rash and polyarthritis improved

39 Treatment of DM Cutaneous Disease Sun-protective measures; avoid photosensitive meds Topical GC (potency depends on severity) Topical calcineurin inhibitors (tacrolimus, pimecrolimus) Antimalarials (hydroxychloroquine or chloroquine); some dermatologists add quinacrine Oral glucocorticoids (varying doses) No Clinical Response after 1-3 months? Yes 2 nd Line Methotrexate (oral/sq) MMF 3 rd Line IVIG Tacrolimus Cyclophosphamide Rituximab 4 th Line Tofacitinib Apremilast Taper prednisone by 20-25% monthly to minimum effective dose

40 Myositis-specific autoantibodies Myositis specific autoantibodies X Anti-synthetase syndrome Necrotizing Clinical phenotypes in adults and children Amyopathic Dermatomyositis Fever Myositis myopathy dermatomyositis Rash Raynauds Arthropathy Lung fibrosis Mechanics hands +/- DM rash High CK Rash sine myositis Hypomyopathic Rash precedes myositis Malignancy Calcinosis/vasculitis (children) Jo-1 Anti-SRP Anti-SAE Anti-NXP-2 Zo EJ Anti-synthetases YRS PL-7 Anti-HMGCR Anti-MDA-5 Anti-TIF1g Anti-Mi-2 KS OJ PL-12 Slide courtesy of Drs. Chinoy and Gunawardena

41 Anti-CADM-140 (anti-mda-5) 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? Cytoplasmic protein that senses viral RNA and induces production of type I interferon Involved in innate immune defense against viruses

42 Anti-CADM-140 (anti-mda-5) 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? Cytoplasmic protein that senses viral RNA and induces production of type I interferon Involved in innate immune defense against viruses Supports role of a viral trigger

43 Anti-MDA-5 Novel cutaneous phenotype of palmar papules and cutaneous ulcerations severe vasculopathy Fiorentino, J Am Acad Derm, 2011

44 Case Two Summer, 2012: Photosensitive rash in 58 yo WF January, 2013: Polyarthritis; mild muscle weakness; rash of DM nl CK; Jo-1, ANA and SSA/B all negative improves on low dose prednisone/mtx May, 2013: DM rashes worse; faint basilar crackles on exam (no pulmonary sx); mild weakness Recommended 20mg prednisone and MMF HRCT/PFTs

45 June 6

46 Case Two July 1: Presents to local ED feeling very SOB CXR opacified In one day, she is up to 12 liters/min O 2 Contacted by rheumatologist Rash a little different

47

48 Case Two July 1: Presents to local ED feeling very SOB CXR opacified In one day, she is up to 12 liters/min O 2 Contacted by rheumatologist Rash a little different Recommend pulse steroids, cytoxan and rituximab

49 July 2

50 July 2 June 6

51 June 6 July 2 Anti- MDA-5 positive

52 Anti-MDA-5 Positivity is Associated with a Poor Pulmonary Outcome MDA5 (-) (n=106) MDA5 (+) (n=16) p<0.001 Moghadam-Kia, Arth Care Rsch, 2016

53 Myositis-specific autoantibodies Myositis specific autoantibodies Anti-synthetase syndrome Fever Myositis Raynauds Arthropathy Lung fibrosis Mechanics hands +/- DM rash X Necrotizing myopathy High CK Clinical phenotypes in adults and children X Amyopathic dermatomyositis Rash sine myositis Hypomyopathic Rash precedes myositis Dermatomyositis Rash Malignancy Calcinosis/vasculitis (children) Jo-1 Anti-SRP Anti-SAE Anti-NXP-2 Zo EJ Anti-synthetases YRS PL-7 Anti-HMGCR Anti-MDA-5 Anti-TIF1g Anti-Mi-2 KS OJ PL-12 Slide courtesy of Drs. Chinoy and Gunawardena

54 Anti-synthetase Syndrome Defines a clinically homogeneous patient population: Fever Myositis Arthritis (misdiagnosed as RA) Raynaud phenomenon Mechanic s hands ILD

55 Clinical Features: Anti-synthetase Syndrome

56 But the skin rash(es) and the myositis may be subtle and the clinical presentation may be lung dominant

57 Case Three 1/2001: 39 yo WF admitted to hospital with 5 weeks of fever ( ) and myalgias; extensive w/u negative except for low titer ANA and mild basilar fibrosis; leaves hospital with FUO frustrated by lack of diagnosis

58 Case Three 1/2001: 39 yo WF admitted with 5 weeks of fever ( ) and myalgias; extensive w/u negative except for low titer ANA and mild basilar fibrosis; leaves hospital with FUO frustrated by lack of diagnosis 3/2001 (office): worsening myalgias and arthralgias, small pleural effusions, fever, Raynaud phenomenon. Dx as UCTD and given empiric prednisone

59 Case Three 1/2001: 39 yo WF admitted with 5 weeks of fever ( ) and myalgias; extensive w/u negative except for low titer ANA and mild basilar fibrosis; leaves hospital with FUO frustrated by lack of diagnosis 3/2001 (office): worsening myalgias and arthralgias, small pleural effusions, fever, Raynaud phenomenon. Dx as UCTD and given empiric prednisone 4/2001: Increased SOB with more prominent diffuse pulmonary infiltrates; subtle Gottron changes; anti-pl-12 autoantibody identified

60 Case Three: Subsequent Course Worsening infiltrates and deteriorating PFTs PFTs: FVC 56%, FEV-1 52%, DLCO 40% Responded to glucocorticoids and tacrolimus Skin rash, joint symptoms and fever never return Never developed myositis Raynaud is mild and most recent PFTs (1/2018) FVC 75%; FEV-1 87%; DLCO 78% Echo with nl PAS (25mmHg) Currently on tacrolimus, no prednisone

61 Making the Diagnosis of Autoimmune ILD Not everyone will present with the classic anti-synthetase syndrome

62 Anti-synthetase Autoantibodies Antibody Antigen (trna synthetase) Prevalence in IIM (%) Jo-1 histidyl PL-7 threonyl <5 PL-12 alanyl <5 OJ isoleucyl <5 EJ glycyl <5 KS asparaginyl <1 Tyr tyrosyl <1 Zo phenylalanyl < 1

63 University of Pittsburgh Anti-Synthetase Cohort Autoantibody Number (% synthetases) Jo (60%) PL (16%) PL-7 27 (12%) EJ 11 (5) OJ 6 (3) KS 9 (4) Total Synthetases 229

64 University of Pittsburgh Anti-Synthetase Cohort Autoantibody Number (% synthetases) Jo (60%) PL (16%) PL-7 27 (12%) EJ 11 (5) OJ 6 (3) KS 9 (4) Total Synthetases 229

65 Initial CTD Diagnosis in Anti-Syn Cohort Jo-1 n=122 Non-Jo-1 n=80 SSc 13% PM 22% DM 24% 17% PM 59% Overlap or UCTD 48% DM 17% PM DM Overlap or UCTD SSc Aggarwal, Ann Rheum Dis, 2014

66 Initial CTD Diagnosis in Anti-Syn Cohort Jo-1 n=122 Non-Jo-1 n=80 SSc 13% PM 22% DM 24% 17% PM 59% Overlap or UCTD 48% DM 17% PM DM Overlap or UCTD SSc Myositis UCTD/Overlap Scleroderma Jo-1 83% 17% 0% Non-Jo-1 39% 48% 13% p<0.001 Aggarwal, Ann Rheum Dis, 2014

67 Survival is worse in non Jo-1 than Jo-1 patients Jo-1 non Jo-1 Aggarwal, Ann Rheum Dis, 2014

68 Survival is worse in non Jo-1 than Jo-1 patients Jo-1 non Jo-1 Diagnosis delay (years) Jo-1 non Jo-1 p value 0.4 ( ) 1.0 ( ) <0.01 Aggarwal, Ann Rheum Dis, 2014

69 Cause of Death in Anti-Synthetase Cohort Infection 6% Cancer 9% Atherosclerosis 9% Unknown 6% Pulmonary fibrosis 49% CTD kidney 3% Pulmonary HTN 11% CTD heart 5% In synthetase (+) pts pulmonary disease was most common cause of death Aggarwal, Ann Rheum Dis, 2014

70 Synthetase Positive Patients: Jo-1 vs. non-jo-1 Non Jo-1 synthetase (+) patients frequently present with non-myositis symptoms and may never manifest them. Diagnosis of a specific CTD is delayed in non-jo-1 synthetase (+) patients perhaps leading to worse survival. Synthetase (+) patients, whether Jo-1 or non Jo-1 have increased pulmonary morbidity and mortality.

71 Classification of Myositis Adult polymyositis Adult dermatomyositis Amyopathic Dermatomyositis Juvenile myositis (DM >> PM) Malignancy-associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) Anti-HMGCR Anti-SRP

72 Are there autoantibody markers that identify patients with malignancyassociated myositis?

73 Anti-p155/140 (anti-tif1-γ) Autoantibody Adults: Associated with severe cutaneous DM and cancer associated myositis JDM: Severe cutaneous involvement including ulceration, edema and calcinosis But cancer associated myositis is not seen in JDM

74 But we were seeing patients with TIF1-γ that did not have malignancy

75 Aggarwal, Rheumatology, 2014

76 Aggarwal, Rheumatology, 2014

77 Do Quantitative TIF1-γ ELISA Titers Predict Cancer Associated Myositis?

78 Anti-TIF1-γ Titers Predict Cancer 60 p = % with Cancer TIF1 negative p = TIF1 low positive (<50) TIF1 high positive ( 50) Cancer in Dermatomyositis Aggarwal et al. ACR 2012

79 Myositis-specific autoantibodies Myositis specific autoantibodies Clinical phenotypes in adults and children Anti-synthetase syndrome Necrotizing Amyopathic Dermatomyositis Fever Myositis myopathy dermatomyositis Rash Raynauds Arthropathy Lung fibrosis Mechanics hands +/- DM rash High CK Rash sine myositis Hypomyopathic Rash precedes myositis Malignancy Calcinosis/vasculitis (children) Jo-1 Anti-SRP Anti-SAE Anti-NXP-2 Zo EJ Anti-synthetases YRS PL-7 Anti-HMGCR Anti-MDA-5 Anti-TIF1g Anti-Mi-2 KS OJ PL-12 Slide courtesy of Drs. Chinoy and Gunawardena

80 Myositis Treatment: Beyond Steroids, Methotrexate and Azathioprine

81 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 Also consider mtx/mmf combination (anecdotal)

82 Mycophenolate Mofetil in Myositis (2-3 grams/day) 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

83 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 Might be the drug of choice in statin-associated IMNM Wang, Clin Rheumatol, 2012

84 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

85 RIM Trial Summary Primary and secondary endpoints were not achieved 83% of refractory adult and juvenile myositis patients (n=200) met the Definition of Improvement in this trial There was a significant glucocorticoid sparing between the baseline dose and the dose at study conclusion Rituximab was generally well tolerated Oddis, Arth Rheum, 2013

86 Myositis Autoantibody Subsets Predict Response to Rituximab Probability of Not Meeting DOI Primary and strongest predictors of response were Jo-1 and Mi-2 Aggarwal, A&R, 2014

87 Biologic Agents in Myositis: Selected Trials Oddis & Aggarwal, Nat. Rev. Rheumatol, 2018

88 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 Okiyama & Kohsaka, Arth Rheum, 2009

89 Tocilizumab in the Treatment of Refractory Polymyositis and Dermatomyositis

90 Biologic Agents in Myositis: Selected Trials Oddis & Aggarwal, Nat. Rev. Rheumatol, 2018

91 Ann Rheum Dis, 2018

92 Biologic Agents in Myositis: Selected Trials Oddis & Aggarwal, Nat. Rev. Rheumatol, 2018

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

94 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)

95 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]

96 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]

97 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]

98 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

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

100 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

101 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 Abatacept should also be studied in AILD

102 Abatacept for the Treatment of Myositis-associated Interstitial Lung Disease (Attack My-ILD) Proof-of-concept study: To evaluate the efficacy and safety of abatacept in myositis ILD; randomized, double blind, placebocontrolled 24-week trial followed by a 24-week open-label extension. Sponsor: Bristol Myers Squibb Principal investigator: Rohit Aggarwal Co-investigators: Chester Oddis, Siamak Moghadam-Kia

103 Long-term experience with rituximab in anti-synthetase syndrome-related ILD (Andersson et al, Rheumatology, 2015) Retrospective study

104 112 Syn+ patients 34 Tx with Rtx 30 severe ILD Long-term f/u Cohort 24/30 with 12 mth f/u 19 Jo-1; 3 PL-7; 2 PL-12 18/24 SSA (+) Acute ILD in 50% Rtx generally 2-dose regimen at days 0, 14 Median f/u from Rtx #1 = 52 mths (12-118) Mean # Rtx cycles = 2.7 (1-11) 8/24 received only 1 cycle None got monotherapy with Rtx!!

105 PFTs 24% 22% 17% % increase from baseline Andersson, Rheumatology, 2015

106 HRCT: Lung Parenchymal Involvement Pre and Post Rtx scans in 23/24 50% to 33% [p<0.001] In 5, ILD extent dropped >60% 1 increased (transplanted) Andersson, Rheumatology, 2015

107 PLOS ONE; November, 2015 J Rheum, 2016

108 Approach to treating myositis-associated ILD Oddis & Aggarwal, Nat. Rev. Rheumatol, 2018

109 Future Approaches to Guiding Therapy Take out the heterogeneity of myositis and study relevant disease subsets Better to study autoab subsets than clinical subsets Clinical/immunogenetic homogeneity Perhaps even pathologic uniformity Sequential approach using different agents Targeted biologic therapy Better exercise programs

110 University of Pittsburgh Myositis Center and Collaborators Rheumatology Rohit Aggarwal, MD, MS Siamak Moghadam-Kia, MD Many fellows over the years Pulmonary Kevin Gibson, MD Kristen Veraldi, MD, PhD Daniel Kass, MD Neuropathology David Lacomis, MD Collaborators Dana Ascherman, MD (U. Miami) Japan Masa Kuwana, MD, PhD Shinji Sato, MD Research Coordinators Diane Koontz (database manager) Many others CTD Research Laboratory Zengbiao Qi

111 Thank You

112

113 Pestronk, Curr Opin Rheum, 2011 Pathologic Myositis Classification

114 Aggarwal, Ann Rheum Dis, 2017

115 Aggarwal, Ann Rheum Dis, 2017