mctd

1. DR MADHURI

2.  1972 Sharp and colleagues
 Identified a group of patients who have mixed
clinical features of SLE , SYSTEMIC SCLEROSIS
AND POLYMYOSITIS
 All such patients have high levels of anti extractable
nuclear antigen (ENA) antibodies and good
prognosis
 They named this entity as MIXED CONNECTIVE
TISSUE DISORDER

3.  ANTI U1snRNP AUTOANTIBODIES
 The function of U1snRNP is splicing of
precursor of mrna
 Anti U1snRNP antibody penetrates human
mononuclear cells and induces apoptosis of
auto reactive lymphocytes
 There exists a molecular mimicracy between
rnp antigen and retroviral p30gag antigen

4. AUTO ANTIBODIES TO FREQUENCY
U1snRNP 100%
73 kDa HSP 100%
Casein kinase 15%
Endothelial cells 57%
Spliceosome(A2/hn RNP) 38%
Human endogenous retrovirus p30gag 33%
Phospholipid 15%
Fibrillin -1 34%
Nuclear matrix 100%

5.  General features —
In the early phases of the MCTD
fatigability
myalgias
arthralgias.
Fever — Fever of unknown origin may be the
presenting feature of MCTD

6.  The most common skin change is the Raynaud
phenomenon.
 Raynauds phenomenon accompanied by
sausage shaped fingers and swelling of dorsum
of hand are typical
 Rarely gangrene of hands also seen

9.  sclerodactyly and calcinosis cutis .
 Discoid plaques and malar rash.
 Mucous membrane involvement –
orogenital and buccal ulcerations,

10.  A patient of mtcd with malar rash

11.  joint involvement in MCTD is more common
and frequently more severe than in classic SLE.
 Approximately 60 percent of patients with
MCTD develop an obvious arthritis, often with
deformities .
 Myositis —
Myalgia is a common symptom in patients
with the MCTD syndrome

12. All three layers of the heart may be involved in
MCTD.
 Pericarditis is the commonest clinical
manifestation of cardiac involvement being
reported in 10 to 30% of patients;

13.  The lungs are commonly affected in MCTD with involvement in about 75 percent of
patients.
• Pleural effusions
• Pleuritic pain
• Pulmonary hypertension
• Interstitial lung disease
• Alveolar hemorrhage
• Diaphragmatic dysfunction
• Aspiration pneumonitis/pneumonia
• Obstructive airways disease
• Pulmonary vasculitis

14.  The absence of severe renal disease is a
hallmark of MCTD.
 Some degree of renal involvement occurs in
about 25 percent of patients.
 Membranous nephropathy is the most
common finding.

15. • Approximately 75% of patients have a low-grade
anemia.
•Leukopenia, mainly affecting the lymphocyte
series, is a common finding.
•The majority of patients have
hypergammaglobulinemia.
.Less common problems include thrombocytopenia,
hemolytic anemia

16.  40% prevalence of flares during pregnancy
 Small for gestational age infants occurred in
50% of pregnancies.
 The mechanism for pregnancy complications is
probably an autoimmune reaction against
placental tissues.

17.  Features of SLE, systemic sclerosis, RA, and
polymyositis
 Four different diagnostic criteria have been
proposed
 Sharp
 Kasukawa
 Alarcon-Segovia
 Kahn
 Highest sensitivity (62%) and specificity (86%)
with Alarcon-Segovia and Kahn

18.  Major Criteria
 Myositis
 Pulmonary
Involvement
 Raynaud phenomenom
or esophageal
dysmobility
 Swollen hands or
sclerodactyly
 High anti-U1-RNP with
negative anti-Sm
 Definite – 4 major plus
serology
 Probable – 3 major or 2 major
(1st 3 listed) and 2 minor; and
serology
 Minor Criteria
 Alopecia
 Leukopenia
 Anemia
 Pleuritis
 Pericarditis
 Arthritis
 Trigeminal Neuralgia
 Malar Rash
 Thrombocytopenia
 Mild Myositis
 h/o swollen hands

19.  Clinical Criteria 3/5 (must have synovitis or myositis)
 Edema of the hands
 Synovitis
 Myositis
 Raynaud’s phenomenon
 Acrosclerosis
 Serologic: high titers of anti-U1 RNP

20.  COMMON SYM
 1)RAYNAUDS PHENOMENON
 2)SWOLLEN FINGERS OR HANDS
 ANTI snRNP AB +
 MIXED SYM
 1) SLE LIKE FINDINGS
 POLYARTHRITIS,LYMPHADENOPATHY,FACIAL ERYTHEMA,PERICARDITIS OR PLUERITIS,THROMBOCYTOPENIA
 2)SSC LIKE FINDINGS
 SCLERODACTYLY,PULMONARY FIBROSIS,RESTRICTIVE CHANGES OF LUNG,HYPOMOBILITY OF ESOPHAGES
 3)PM LIKE FINDINGS
 MUSCLE WEAKNESS,ELEVATED LEVELS OF CPK
 ATLEAST 1 OF THE 2 COMMON SYMPTOMS PLUS POSITIVE FOR ANTI-snRNP
PLUS 1 OR MORE OF THE MIXED SYMPTOMS IN ATLEAST 2 OR 3 DISEASE
CATEGORIES

21.  All patients have the speckled type of antinuclear antibody
together with a high titre of antibody to ENA, which is
sensitive to digestion with ribonuclease (RNase), unlike the
ENA antibodies found in patients with SLE.
 Different molecular forms of U1-RNP may be associated
with different clinical variants
 Ro and La antibodies are frequently found in association
with sicca symptoms
 Precipitating antibodies PM-1 and Ku occur in
polymyositis/systemic sclerosis overlap
 SL-Ki in patients with SLE, scleroderma and the sicca
syndrome

22.  Immune complexes occur in 90% ofpatients
 T cells are decreased
 Complement levels are normal.
 Sometimes, anti-DNA antibody occurs in low titre,
but this usuallydisappears with steroid therapy.
 Antiendothelial antibodies are associated with
abnormal pulmonary, neurological and cardiac
function, particularly pulmonary hypertension and
related to spontaneous abortion in female patients
 HLA-DR4 is found more commonly in patients
with arthritis

23.  Immunohistology of uninvolved skin, where there is
basement membrane staining with IgG or M, may be
helpful in distinguishing MCTD from uncomplicated
systemic sclerosis where staining is absent
 Direct immunofl uorescence study of apparently
normal skin reveals particulate (‘speckled’) epidermal
nuclear staining, and this correlates with high titres of
anti-RNP. Occasionally, epidermal nucleolar staining
occurs. Patients with these features show a high
incidence of persistent, diffuse, non-scarring and focal
alopecia, hyper- and hypopigmentation with follicular
retention of pigment, swollen hands with
sclerodactyly, and lesions ofDLE.

24.  The overall goal of therapy is to control
symptoms and to maintain function.
 Monitoring for development of complications,
such as pulmonary hypertension or infection, is
important.

25. Medication
 The goals of pharmacotherapy are to reduce
morbidity and to prevent complications.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
 These agents reduce pain and inflammation and
allow for improvement in mobility and function.

26. Corticosteroids
 These agents are reserved for more active or
severe disease.
 Corticosteroids are occasionally helpful during
early stage of disease
 Administration of 30 mg or more of steroids
carries good prognosis than lower doses

27. Proton pump inhibitors
 Esophageal reflux symptoms can be controlled
effectively with these agents
Calcium channel blocking agents
 Avoiding exposure to cold temperatures and
using long-acting calcium channel blocking
agents may control Raynaud phenomenon

28. Phosphodiesterase (type 5) Enzyme Inhibitor
Eg-sildenafil
 Phosphodiesterase inhibitors can relief
symptoms of pulmonary hypertension and
Raynaud phenomenon in patients with MCTD.

29. Endothelin Receptor Antagonist
Eg- Ambrisentan
 These agents may be helpful for managing
pulmonary hypertension in patients with
MCTD
 Improves exercise ability..

30. Prostaglandins
Eg-Epoprostenol
 These agents may be useful for managing
pulmonary hypertension in patients with
MCTD.
 Strong vasodilator of all vascular beds.
 Decrease platelet clumping in the lungs by
inhibiting platelet aggregation.

31. Cytotoxic agents
 Major organ involvement may require moderate-
to-high divided daily doses of cytotoxic agents.
 Recent reports suggest that, in contrast to primary
or scleroderma-associated pulmonary
hypertension, a subset of MCTD patients with
pulmonary hypertension may respond well to
aggressive immunosuppression with cytotoxic
agents.

32.  1/3 rd of the patients have mild self limited
disease accompanied by disappreance of anti-
U1 sn RNP antibodies
 Another 1/3 rd develop severe progressive
disease
 The most severe clinical manifestation is
pulmonary hypertension which contributes to
premature death
 Scleroderma renal crisis,myocarditis and
widespread vasculitis are other causes of death