Myositis and Autoimmune ILD

2018 AURA Annual Meeting Sedona, Arizona

June 2, 2018

Chester V. Oddis, MD Director, Myositis Center University of Pittsburgh

Disclosures

• Genentech: Clinical trial support • Idera: Clinical trial participant • Mallinckrodt: Clinical trial support; Advisory

Board

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

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)

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

Rashes of Dermatomyositis Rashes of Dermatomyositis

Cuticular Thickening and

Periungual Erythema

Nail fold capillary abnormality

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)

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)

• 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

Polymyositis Mimics

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

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

Neurology, 2003

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

Medicine, 2005

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

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)

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

Necrotizing Myopathy

Kassardjian, JAMA Neurol, 2015

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

Case One • March, 2010 (1st 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

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

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

Christopher-Stine, Arth Rheum, 2010

Controls in lanes 5 and 10

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

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 2013 – 2017; went back on mtx and IVIg; CK still elevated

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 2013 – 2017; went back on mtx and IVIg; CK still elevated

Pt is anti-HMGCR autoAb positive

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”

Muscle Pathology of SRP Antibody Subset

• Necrotizing myopathy without inflammation

Dimitri, Muscle and Nerve, 2007

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

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

Sometimes the skin

disease can be the most

dominant feature

DM Scalp Rash

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)

2nd Line

Methotrexate (oral/SQ) MMF

3rd Line

IVIG Tacrolimus Cyclophosphamide Rituximab

Taper prednisone by 20-25% monthly to minimum

effective dose

Yes No

Clinical Response after 1-3 months?

Apremilast in DM

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

Tofacitinib in DM: Case 1

• 55 yo female • Failed or partially responsive to GC, mtx,

HCQ, aza, MMF, chloroquine, Acthar gel, tacrolimus, IVIg

3 months

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

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

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)

2nd Line

Methotrexate (oral/SQ) MMF

3rd Line

IVIG Tacrolimus Cyclophosphamide Rituximab

Taper prednisone by 20-25% monthly to minimum

effective dose

Yes No

Clinical Response after 1-3 months?

4th Line Tofacitinib Apremilast

Myositis specific autoantibodies Clinical phenotypes in adults and children

Myositis-specific autoantibodies

Anti-synthetases

PL-12 OJ KS

PL-7

EJ

Jo-1

Zo

YRS

Anti-SRP

Anti-HMGCR Anti-MDA-5

Anti-SAE Anti-NXP-2

Anti-Mi-2 Anti-TIF1g

Necrotizing

myopathy

High CK

Amyopathic

dermatomyositis

Rash sine myositis

Hypomyopathic

Rash precedes myositis

Dermatomyositis

Rash

Malignancy

Calcinosis/vasculitis (children)

Anti-synthetase syndrome

Fever

Raynauds

Lung fibrosis

Myositis

Arthropathy

Mechanics hands

+/- DM rash

Slide courtesy of Drs. Chinoy and Gunawardena

X

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

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

Anti-MDA-5

• Novel cutaneous phenotype of palmar papules and cutaneous ulcerations – severe vasculopathy

Fiorentino, J Am Acad Derm, 2011

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

June 6

Case Two

• July 1: Presents to local ED “feeling very SOB”

• CXR ‘opacified’

• In one day, she is up to 12 liters/min O2

• Contacted by rheumatologist – Rash a little different

Case Two

• July 1: Presents to local ED “feeling very SOB”

• CXR ‘opacified’

• In one day, she is up to 12 liters/min O2

• Contacted by rheumatologist – Rash a little different

• Recommend pulse steroids, cytoxan and rituximab

July 2

July 2

June 6

July 2

June 6

Anti- MDA-5 positive

Anti-MDA-5 Positivity is Associated with a Poor Pulmonary Outcome

p<0.001

MDA5 (-) (n=106)

MDA5 (+) (n=16)

Moghadam-Kia, Arth Care Rsch, 2016

Myositis specific autoantibodies Clinical phenotypes in adults and children

Myositis-specific autoantibodies

Anti-synthetases

PL-12 OJ KS

PL-7

EJ

Jo-1

Zo

YRS

Anti-SRP

Anti-HMGCR Anti-MDA-5

Anti-SAE Anti-NXP-2

Anti-Mi-2 Anti-TIF1g

Necrotizing

myopathy

High CK

Amyopathic

dermatomyositis

Rash sine myositis

Hypomyopathic

Rash precedes myositis

Dermatomyositis

Rash

Malignancy

Calcinosis/vasculitis (children)

Anti-synthetase syndrome

Fever

Raynauds

Lung fibrosis

Myositis

Arthropathy

Mechanics hands

+/- DM rash

Slide courtesy of Drs. Chinoy and Gunawardena

X X

Anti-synthetase Syndrome

• Defines a clinically homogeneous patient population: – Fever – Myositis – Arthritis (misdiagnosed as RA) – Raynaud phenomenon – Mechanic’s hands – ILD

Clinical Features: Anti-synthetase Syndrome

But … the skin rash(es) and the myositis

may be subtle and the clinical

presentation may be ‘lung dominant’

Case Three • 1/2001: 39 yo WF admitted to hospital with 5

weeks of fever (103-1040) and myalgias; extensive w/u negative except for low titer ANA and mild basilar fibrosis; leaves hospital with FUO frustrated by lack of diagnosis

Case Three • 1/2001: 39 yo WF admitted with 5 weeks of

fever (103-1040) 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

Case Three • 1/2001: 39 yo WF admitted with 5 weeks of fever

(103-1040) 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

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

Making the Diagnosis of Autoimmune ILD

Not everyone will present with the classic anti-synthetase

syndrome

Anti-synthetase Autoantibodies

Antibody Antigen (tRNA synthetase)

Prevalence in IIM (%)

Jo-1

histidyl

20-30

PL-7 threonyl <5 PL-12 alanyl <5

OJ isoleucyl <5 EJ glycyl <5 KS asparaginyl <1 Tyr tyrosyl <1 Zo phenylalanyl < 1

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

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

Initial CTD Diagnosis in Anti-Syn Cohort

Aggarwal, Ann Rheum Dis, 2014

DM 24%

17%

Jo-1 n=122

PM 22%

DM 17% Overlap or UCTD

48%

SSc 13%

Non-Jo-1 n=80

PM DM Overlap or UCTD SSc

PM 59%

Initial CTD Diagnosis in Anti-Syn Cohort

Aggarwal, Ann Rheum Dis, 2014

DM 24%

17%

Jo-1 n=122

PM 22%

DM 17% Overlap or UCTD

48%

SSc 13%

Non-Jo-1 n=80

PM DM Overlap or UCTD SSc

PM 59%

Myositis UCTD/Overlap Scleroderma Jo-1 83% 17% 0% Non-Jo-1 39% 48% 13%

p<0.001

Survival is worse in non Jo-1 than Jo-1 patients

Aggarwal, Ann Rheum Dis, 2014

Jo-1

non Jo-1

Survival is worse in non Jo-1 than Jo-1 patients

Aggarwal, Ann Rheum Dis, 2014

Jo-1

non Jo-1

Jo-1 non Jo-1 p value

Diagnosis delay (years) 0.4 (0.2-0.8) 1.0 (0.4 – 5.1) <0.01

Pulmonary fibrosis

49%

Pulmonary HTN 11%

CTD heart 5%

CTD kidney

3%

Cancer 9%

Infection 6%

Atherosclerosis 9%

Unknown 6%

Cause of Death in Anti-Synthetase Cohort

In synthetase (+) pts pulmonary disease was most common cause of death

Aggarwal, Ann Rheum Dis, 2014

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.

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

Are there autoantibody markers that identify patients with malignancy-

associated myositis?

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

But we were seeing patients with

TIF1-γ that did not have malignancy

Aggarwal, Rheumatology, 2014

Aggarwal, Rheumatology, 2014

Do Quantitative TIF1-γ ELISA Titers

Predict Cancer Associated

Myositis?

Anti-TIF1-γ Titers Predict Cancer

Aggarwal et al. ACR 2012

6 10 25 50

100 125

75 0

10

20

30

40

50

60

TIF1 negative TIF1 low positive (<50)

TIF1 high positive (≥50)

% with Cancer

p = 0.67

p = 0.0002

Cancer in Dermatomyositis

Myositis specific autoantibodies Clinical phenotypes in adults and children

Myositis-specific autoantibodies

Anti-synthetases

PL-12 OJ KS

PL-7

EJ

Jo-1

Zo

YRS

Anti-SRP

Anti-HMGCR Anti-MDA-5

Anti-SAE Anti-NXP-2

Anti-Mi-2 Anti-TIF1g

Necrotizing

myopathy

High CK

Amyopathic

dermatomyositis

Rash sine myositis

Hypomyopathic

Rash precedes myositis

Dermatomyositis

Rash

Malignancy

Calcinosis/vasculitis (children)

Anti-synthetase syndrome

Fever

Raynauds

Lung fibrosis

Myositis

Arthropathy

Mechanics hands

+/- DM rash

Slide courtesy of Drs. Chinoy and Gunawardena

Myositis Treatment:

Beyond Steroids, Methotrexate and

Azathioprine

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)

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

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

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

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

Myositis Autoantibody Subsets Predict Response to Rituximab

Prob

abili

ty o

f Not

Mee

ting

DO

I

Primary and strongest predictors of response

were Jo-1 and Mi-2

Aggarwal, A&R, 2014

Biologic Agents in Myositis: Selected Trials

Oddis & Aggarwal, Nat. Rev. Rheumatol, 2018

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

Tocilizumab in the Treatment of Refractory Polymyositis and

Dermatomyositis

Biologic Agents in Myositis: Selected Trials

Oddis & Aggarwal, Nat. Rev. Rheumatol, 2018

Ann Rheum Dis, 2018

Biologic Agents in Myositis: Selected Trials

Oddis & Aggarwal, Nat. Rev. Rheumatol, 2018

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

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)

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]

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]

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]

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

Tacrolimus in Myositis and ILD

Parameter p-value FVC <0.0001 FEV-1 <0.0001 DLCO 0.0046 CK <0.0001 MMT 0.06 CS Dose <0.0001

Wilkes, Arth Rheum, 2005

Retrospective study of 13 synthetase (+) pts (12 with Jo-1)

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

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

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, placebo-controlled 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

Long-term experience with rituximab in anti-synthetase

syndrome-related ILD (Andersson et al, Rheumatology, 2015)

Retrospective study

112 Syn+ patients

34 Tx with Rtx

24/30 with 12 mth f/u

30 severe ILD

Long-term f/u Cohort

• 19 Jo-1; 3 PL-7; 2 PL-12 • 18/24 SSA (+) • Acute ILD in 50% • 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!!

Rtx generally 2-dose regimen at days 0, 14

PFTs 24% 22% 17% % increase from

baseline

Andersson, Rheumatology, 2015

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

PLOS ONE; November, 2015

J Rheum, 2016

Approach to treating myositis-associated ILD

Oddis & Aggarwal, Nat. Rev. Rheumatol, 2018

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

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

Thank You

Pathologic Myositis Classification

Pestronk, Curr Opin Rheum, 2011

Aggarwal, Ann Rheum Dis, 2017

Aggarwal, Ann Rheum Dis, 2017