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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
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