Mixed Connective Tissue Disease?

Mark Wener, MD

Rheumatology Division, Medicine

Immunology Division, Lab Medicine

MCTD – Original Description

American Journal of Medicine 1972; 52: 148-159

MCTD: Sharp’s Original Description• Clinical overlap syndrome, with features of:

– Scleroderma: Raynaud’s, sclerodactyly, GI

– Myositis: myalgias, elevated CK, abnormal muscle biopsy

– Lupus: leukopenia, rashes (not photosensitive), but NOT renal, NOT CNS

– Arthralgias/arthritis

– Responds to corticosteroids, good prognosis

– Demographics: women 21/men 4, age 36 (13-66)

Raynaud’s Phenomenon

Edematous Phase of

Sclerodactyly

Sclerodactyly / Acrosclerosis

MCTD: Sharp’s Original Description• Clinical overlap syndrome, with features of:

– Scleroderma: Raynaud’s, sclerodactyly, GI– Myositis: myalgias, elevated CK, abnormal muscle

biopsy– Lupus: leukopenia, rashes (not photosensitive),

but NOT renal, NOT CNS– Arthralgias/arthritis– Responds to corticosteroids, good prognosis

• Lab: High-titer speckled ANA, with– Autoantibody to extractable nuclear antigen (ENA)

which contains RNA + protein = ribonucleoprotien(RNP antigen). NOT anti-Sm, NOT anti-DNA

• Demographics: women 21/men 4, age 36 (13-66)

ANA, Speckled Pattern

ANA Patterns

Homogeneous Nucleolar

Speckled Centromere

1000x

Extractable Nuclear Antigens ‘ENA’• Nuclei (thymus)

– ‘Extract’ with saline, i.e. create pool of nuclear antigens that are soluble in normal saline

– ENA subtypes (1972)

• Smith (Sm) antigen: identical pattern as antibody from lupus pt Ms. Smith

–Antigen is destroyed by trypsin, i.e. has protein, not by RNase (no RNA)

• RNP antigen: antigen destroyed by trypsin and by RNase = ribonucleic acid-protein complex

–High levels associated with MCTD

IFA Patterns & Ags Associated

Centromere = centromere antigens.

Homogeneous: DNA, chromatin, histones, etc.

Speckled: Extractable nuclear antigens (Sm, RNP, SS-A, SS-B), Scl-70, RNA polymerase III, etc.

Nucleolar: scleroderma (fibrillarin, Th/To, PM/Scl, Scl70, etc.

Cytoplasmic: ribosomal P, Jo-1

IFA Patterns & Ags Associated

Centromere = centromere antigens.

Homogeneous: DNA, chromatin, histones, etc.

Speckled: Extractable nuclear antigens (Sm, RNP, SS-A, SS-B), Scl-70, RNA polymerase III, etc.

Nucleolar: scleroderma (fibrillarin, Th/To, PM/Scl, Scl70, etc.

Cytoplasmic: ribosomal P, Jo-1

MCTD Classification Criteria• No official criteria, 5 proposed sets, with 5-15

clinical criteria.• Alarcon-Segovia’s simplest, sensitive• Serologic criterion: anti-RNP at high titer. • Clinical criteria

1. Edema of the hands, 2. Synovitis3. Myositis4. Raynaud’s phenomenon5. Acrosclerosis

Serologic criterion plus at least three of five clinical criteria, including synovitis or myositis.

MCTD: Typical Clinical Features• Rheumatic disease ‘overlap syndrome’• High levels of antiRNP in isolation• Frequent clinical features:

– Raynauds (almost 100%)– Arthritis/arthralgias– Sclerodactyly– Pulmonary hypertension, interstitial lung disease– Low grade myositis – GI: pseudo-obstruction, bacterial overgrowth– Rash: variable. Malar, not usually photosensitive– Cardiac, variable

MCTD: Course & Treatment

• Course variable

• Treatment requirement variable, often requires immunosuppressives

– No randomized trials

• Pulmonary hypertension often prominent,mayrequire treatment

MCTD: Followup of Original Cohort

MCTD Followup of Original Cohort, N=25

• Alive N= 14

– Disease duration 8-25 years (average 15)

– Age at onset 32 (13-45), at followup 46 (21-65)

• Dead, N= 8

– Disease duration 3-15 years (average 8)

– Age at onset 37 (12-65), at death 44 (20-69)

MCTD: Long-Term Followup of Original Patients

Final Diagnosis N

MCTD 3

Systemic Sclerosis (SSc) 5

SSc with mild myositis 3

SLE 0 (2 SLE overlap)

RA 1

Asymptomatic 4

Unknown 5

MCTD: Stanford Cohort Long-Term

Sharp: Long-Term Followup of Missouri Cohort

Long-Term Followup of Missouri Cohort of MCTD

Long-Term Followup of Missouri Cohort of MCTD

Clinical Feature Cumulative %

Sclerodactyly 49

Diffuse scleroderma

19

Pulmonary hypertension

23

Renal disease 11

Nervous system disease

17 (mild, mostly)

Raynauds 96

Arthritis/Arthralgia 96

Genetics of MCTD

• More frequently associated with HLA-DR4 (like RA)

• Relative risk modest (2-3)

• Not seen in all studies

• Genome-wide screens not reported

MCTD vs UCTD

• UCTD = Undifferentiated connective tissue disease

– Vague criteria

– No antibody signature

• MCTD = characteristic overlap syndrome

– Anti-RNP highly linked

U1 RNA

U1 RNP

SpliceosomeModel

Scleroderma AutoantibodiesSpeckled: RNP, Scl70 Nucleolar: several Centromere

Gabrielli A et al. N Engl J Med 2009;360:1989-2003

Autoantibodies & Scleroderma Prognosis

Modified from Reveille, 2003, Arthritis Res Ther 2003; 5:80-93

Scl70Th/ToRNA polymerase

CentomerePM-Scl

FibrillarinU3-RNPRNP (U1-RNP)

MCTD: A Scleroderma Subset?

• Sclerodactyly > diffuse cutaneous disease• Pulmonary hypertension• Low –grade myositis• Arthralgias/Arthritis• Esophageal disease • Gut motility

• Treatment based on site and severity of organ involvement, not based on dx of ‘MCTD’

Gabrielli A et al. N Engl J Med 2009;360:1989-2003

Autoantibodies & Scleroderma Clinical Features

‘MCTD?’

Methotrexate Hepatotoxicity• Histology:

– steatosis

– stellate cell hypertrophy

– anisonucleosis (nuclei of varying sizes)

– hepatic fibrosis

• Transaminase elevation ~`10%

– Often mild and transient

– Usually resolves within one month of stopping MTX