Overlap syndromes
Structure of the presentation
Definition of overlap syndromes
Concept of diseases with overlapping features
Short description of diseases overlapping with
myositis
Specific overlap syndromes with myositis
Mixed connective tissue disease
Treatment
Questions, discussion
Overlap syndromes
(with PM/DM)
Syndromes where clinical or laboratory signs and
symptoms of another defined connective tissue
disease occur.
Such as
systemic lupus erythematosus (SLE),
scleroderma (SSc),
rheumatoid arthritis (RA),
Sjgrens syndrome (SjS)
ChurgStrauss arteritis, thrombotic thrombocytopenic purpura,
antiphospholipid antibody syndrome and autoimmune thyroid
disease.
Idiopathic inflammatory myopathies
Primary idiopathic polymyositis
Primary idiopathic dermatomyositis
Juvenile poly/dermatomyositis
Myositis associated with another CTD (10-60%)
Myositis associated with malignancy
Inclusion body myositis
Bohan A, Peter JB et al. N Engl J Med 1975; 292: 3447, Medicine (Baltimore) 1977; 56: 25586.
Concept of diseases with overlapping
features
Overlap syndromes
Undifferentiated connective tissue disease (UCTD)
Mixed connective tissue disease (MCTD)
MCTD SLE
UCTD
SjS SSc
PM/DM
Puffy fingers Photosensitive rash
MCTD SLE
UCTD
Arthritis
SjS SSc
Raynauds
Dry eyes PM/DM phenomenon
Muscle weakness
MCTD SLE
UCTD
SjS SSc
PM/DM
Systemic lupus erythematosus (SLE)
An autoimmune multisystem disease characterized by
heterogeneous clinical and laboratory features and a
variable course and prognosis
Immunological abnormalities lead to B cell
hyperactivity, autoantibody production and immune
complex deposition in vital organs
Clinical manifestations encompass constitutional
symptoms as well as any combination of organ
involvement such as skin, mucous membranes, joints,
kidney, brain, serous membranes, lung, heart and
gastrointestinal tract
Classification criteria for SLE
Erythema in the face
Discoid erythema
Photosensitivity
Mouth ulcers
Arthritis
Serositis (pleuritis, pericarditis)
Renal (proteinuria, casts)
Neurological involv. (seizures, psychosis)
Hematology (anemia, leuko-, trombocytopenia)
immunology (anti-dsDNA, anti-Sm, APL aCL, LA, FP
BWR)
Antinuclear antibodies
Hand deformities in SLE
Systemic sclerosis (SSc)
Progressive disease that affects the skin and
connective tissue (including cartilage, bone, fat,
and the tissue that supports the nerves and
blood vessels throughout the body).
increased deposition collagen in interstitium
of small arteries and connective tissue
sclerotic changes in skin and internal organs
SSc - presentation
general and skin
Raynauds phenomenon
edema fingers and hands
skin thickening
visceral manifestations
GI tract, lung, hear, kidneys, thyroid
arthralgias and muscle weakness
CLASSIFICATION OF SYSTEMIC SCLEROSIS
(adapted according to J.R. Seibold, 1994)
I. diffuse skin thickening - trunk, face and limbs
II. limited - skin thickening localized distally of elbows
and knees, with face involvement, CREST
III. sine scleroderma without skin involvement (except
of face), fibrotic changes of visceral organs, vascular
and serological findings.
IV. overlap syndrome - fulfilled criteria of SSc and of SLE, RA or polymyositis
V. undifferentiated connective tissue disease - Raynauds phenomenon with
clinical and/or laboratory abnormalities - anticentromere antibodies, skin
vascular trophic changes
Rheumatoid arthritis (RA)
RA is a chronic, systemic
inflammatory disorder.
Principally affects joints -
synovitis, pannus.
Leads to destruction of
articular cartilage and
bones.
May target also other
tissues and organs (lungs,
pericardium, pleura, sclera).
Nodular lesions
IIMs associated with anti-TNF therapy for RA
Reference Anti-TNF Interval IIM Treatment Outcome Antibodies
Musial 2003 IFX 13 m PM/IP GC Improved RF, dsDNA, Jo-1
Urata 2006 IFX 9m PM/IP GC Improved RF, ANA, Jo-1
Hall 2006 ETN 6m DM GC, AZA, MTX Improved ANA, Jo-1
RF, CCP, ANA,
Liozon 2007 ADA 8m PM GC, MTX Improved
dsDNA, Pm-Scl
Vordenbumen
ADA/ETN 3m IBM GC/RTX Unchanged RF
2010
Brunasso 2010 ADA 48 m DM GC, MTX Improved RF, ANA
ETN Days DM/IP GC, MYP, HCQ Improved RF
ETN 24 m DM GC, RTX RF, ANA
Klein 2010 Improved
ADA 3m DM GC, MTX, HCQ, AZA Improved, not skin ANA
ADA 2m DM/IP GC, HCQ, CYP Improved RF, CCP
Ishikawa 2010 ETN 2m PM/IP GC, CIS Improved CCP, Jo-1
Modified from: Stubgen J-P. J Neurol 2011, on line.
Sjgrens syndrome
Immune mediated destruction of exocrine glands
Primary
- inflammation and destruction of lacrimal and salivary glands
leading to dry mouth and dry eyes (xerophthalmia,
keratoconjunctivitis, xerostomia
other areas - skin, vagina, chronic bronchitis, GI tract, renal
tubules)
- extraglandular manifestations (vasculitis, Raynauds
phenomenon, neuropathy, arthritis, nephropathy, ).
Secondary
- sicca complex - associated with other CTD
Overlap syndrome
CTD Overlap CTD
disease
disease 1 disease 2
Overlap syndrome
Overlap Systemic
Polymyositis disease
PM/Scl scleroderma
SLE SSc
MCTD
PM/DM RA
Overlap syndromes
Classification into overlap syndromes is facilitated by
detection of autoantibodies
Mixed connective tissue disease (MCTD,
Sharps syndrome) (anti-nRNP autoantibodies,
or anti-p70),
Antisynthetase syndrome (ASS) (anti-Jo-1,
anti-PL-7, 12 etc.)
Polymyositis/scleroderma overlap (PM/Scl)
(anti-PM/Scl antibodies)
Scleroderma/polymyositis (anti-Ku antibody)
autoantibody immunofluorescence on HEp-2 cells
speckled, or coarse granular; no staining
U1-RNP of nucleoli and metaphase
chromosomes; high titer
granular cytoplasmic; no nuclear staining
Jo-1 (unless other ANA are simultaneously
present)
nucleolar, plus fine granular staining of
PM-Scl nucleoplasm, no staining of metaphase
chromosomes; often low titer
Ku fine granular, no staining of metaphase
chromosomes; mostly high titer
Prevalence
MCTD it is probably around 10/100 000
ASS constitutes 30% of PM and DM cases.
In MCTD the female:male ratio is about 9:1,
In ASS 2.7:1.
Diagnostic criteria for MCTD
Clinical criteria
Oedema of the hands
Synovitis
Myositis
Raynauds phenomenon
Acrosclerosis
Laboratory criteria
Positive anti-nRNP at a high concentration
Requirements for the diagnosis: Serologic criterion + at least 3 clinical
(In the case that oedema, Raynauds phenomenon and acrosclerosis are combined,
then 4 clinical criteria are required).
Alarcon-Segovia D, et al. J Rheumatol 16:328-334.
Mixed connective tissue disease
Clinical features % of patients
Arthritis/arthralgia 95
Raynauds phenomenon 85
Decreased oesophageal motility Dysphagia, heartburn 67
Impaired pulmonary diffusing capacity 67
Swollen hands 66
Myositis 63
Lymphadenopathy 39
Skin rash 38
Sclerodermatous changes 33
Fever 33
Serositis Pericarditis, pleurisy 27
Splenomegaly 19
Hepatomegaly 15
Neurologic abnormalities Trigeminal neuralgia 10
Renal disease 10
MCTD (signs appear sequentially)
Clinical features % of patients
Arthritis/arthralgia 95
Raynauds phenomenon 85
Decreased oesophageal motility 67
Impaired pulmonary diffusing capacity 67
Swollen hands 66
Myositis 63
Lymphadenopathy 39
Skin rash 38
Sclerodermatous changes 33
Fever 33
Serositis 27
Splenomegaly 19
Hepatomegaly 15
Neurologic abnormalities 10
Renal disease 10
MCTD most important features
Myositis
Fibrosing alveolitis
Pulmonary hypertension
MCTD laboratory
High anti-U1 RNP
Absence of anti-dsDNA, anti-Sm
High immunoglobulins (IgG,
gammaglobulins)
High erythrocyte sedimentation rate
Often rheumatoid factors
(Positive anti-RA33)
Antisynthetase syndrome
Myositis
Interstitial lung disease (89%)
Arthritis (94%)
Raynauds phenomenon (67%)
Fevers (87%)
Mechanics hands (71%)
Anti-Jo-1 similar pathology
Perimysial fragmentation
Macrophage predominance
Perifascicular changes (atrophy, regeneration,
some necrosis)
Normal capillary density
Love LA et al. Medicine 1991;70:360-74, Mozaffar T, Pestronk A. J Neurol Psychiatry 2000;68:472-8.
Serological classification
SRP p200/100
SAE
Mi-2
SEVERE MYOPATHY NXP-2 (p140, MJ)
Jo-1
EIF3, PM complex
SKIN DISEASE++
LUNG DISEASE
Zo p140/56
Anti-synthetase
EJ
autoantibodies
TIF-1 gamma
LUNG DISEASE++
PL-7
YRS SINE MYOSITIS
PL-12 MALIGNANCY
KS
OJ
MDA5, CADM-140
Wa KJ
Adapted from Gunawardena H, Betteridge Z et al.
Possibilities in the treatment of myositis
(Probably) efficacious Probably inefficacious Experimental
Glucocorticoids Plasmapheresis and Anti-TNF
leukapheresis Rituximab
Methotrexate (13+13+13) IL-1 blockade
Azathioprine (8+8) Interferon-beta Leflunomide
Combination AZA+MTX ASCT
IVIg (8+7) Treatment for Raynauds phenomenon:
Cyklosporine A - Often unresponsive to glucocorticoids
Cyclophosphamide - Warmed of
Treatment gloves
pulmonary hypertension:
Tacrolimus - Calcium channel
endothelin receptorblockers, ACE bosentan
antagonists inhibitors or
- Prostaglandin
sitaxentan . infusions
Mycophenolate mofetil
Phosphodiesterase-5 inhibitor sildenafil.
Long-term anticoagulation.
Hydroxychloroquine Tyrosine kinase inhibitor imatinib mesylate
improved pulmonary fibrosis in MCTD.
