MCTD A autoimmune disease with overlapping features of SLE, systemic sclerosis and polymyositis, and presence of the antibody that reacts with U1- ribonucleoprotein (RNP). Diagnostic criteria:- 3 of the followings: synovitis or myositis (1 must be present), edema of hands, Raynaud phenomenon, acrosclerosis and serologic evidence of positive anti-snRNP in atleast moderate titer.(1)
PAH Pulmonary arterial hypertension (PAH) is haemodynamically defined as a resting mean pulmonary arterial pressure >25mmHg with a normal pulmonary capillary wedge pressure of <15mmHg on right heart catheterization. Pulmonary hypertension is suggested when an echocardiogram derived estimate of pulmonary arterial systolic pressure exceeds 40mm Hg at rest.
Pulmonary arterial hypertension Sporadic Familial Related to: Collagen vascular disease Congenital systemic-to-pulmonary shunts (large, small, repaired, or nonrepaired) Portal hypertension HIV infection Drugs and toxins(fenfluramine, amphetamines or cocaine) Others (glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) Pulmonary veno-occlusive disease Pulmonary capillary hemangiomatosisPulmonary venous hypertension Left-sided atrial or ventricular heart disease Left-sided valvular heart disease
Pulmonary hypertension associated with hypoxemia Chronic obstructive pulmonary disease Interstitial lung disease Sleep-disordered breathing Alveolar hypoventilation disorders Long-term exposure to high altitudePHTN sec to chronic thrombotic or embolic disease Thromboembolic obstruction of proximal pulmonary arteries Thromboembolic obstruction of distal pulmonary arteries Pulmonary embolism (tumor, parasites, foreign material)Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)
MCTD: first described as an apparently distinct rheumatic disease syndrome in 1972 (2) Prevalence : 10/100 000 in U.S (3) The female : male ratio is about 9 : 1 (3) The lung is a common target organ in 25–85% of patients with MCTD In MCTD the prevalence of pulmonary arterial hypertension (PAH) is between 20% and 30% (3)
Pathogenesis of MCTD Unclear etiology The expression of intracellular ribonucleoproteins on the cell surface in apoptotic blebs. Immune tolerance breakdown as a result of post- translational modification of the 70 kDa molecule or as a result of molecular mimicry with viral antigens.
Pathogenesis of PAH Impaired smooth muscle Ca channel function. Endothelial cell function damage. Decreased production of vasodilatating nitrogen monoxide and prostacyclin. Increases the production of vasoconstrictor thromboxane A2 and endothelin-1 in the endothelial cells. Vasoconstriction, proliferation of small and medium size arteries, this provoke a predisposition to thrombosis.
Narrowing of the pulmonary arteries and arterioles in the lung specimen
Major clinical features of MCTD % involvementArthritis/ arthralgia 95Raynauds 85Oesophageal involvement 67Impaired lung diffusion 67Swollen hands 66Myositis 63Scleroderma 33Serositis 27Trigeminal neuralgia 25Renal disease 10Cerebral involvement 10
Signs and Symptoms of PAH shortness of breath on exertion fatigue angina syncope and pre-syncope abdominal distension peripheral edema Jugular vein distension accentuated pulmonary component of S2 hepatomegaly and ascites.
Myositis Fibrosing alveolitis Pulmonary hypertension: most common cause of death in MCTD The prognosis for MCTD with PAH is extremely poor, and the mean duration of survival from the onset of the underlying disease is 4.4 years for these patients. (4) Median survival in untreated patients is only 12 months, and the risk of death is nearly tripled. This survival rate is in the range of some malignant diseases and thus highlights the need for early diagnosis and treatment. (5) The tendency of the disease to evolve into one of its sister diseases such as SLE or systemic sclerosis
MCTD Anti-U1RNP antibodies (high titers) Hematological findings: leukopenia, thrombocytopenia and a high erythrocyte sedimentation rate. High immunoglobulin; esp Ig G Complements: N or High Rh factor: high Exclusion criteria : presence of anti-Sm and anti-DNA antibodies.
PAH Transthoracic Doppler echocardiography is the technique of choice for early evaluation of PAH because it is noninvasive and allows serial determinations of the mean PAP. It should be repeated every 1-2 yrs. TTE estimates the right ventricular systolic pressure (RVSP), which is equivalent to the pulmonary artery systolic pressure in the absence of pulmonary outflow obstruction, by measuring the systolic regurgitant tricuspid flow velocity. TRV jet > 2.5 m/sec with unexplained dysnea or TRV jet > 3 m/sec: indicates the need RHC
While TTE is an excellent screening tool for PAH, it has limitations: RVSP increases with age and body mass index RVSP is reported to be 28+/-5mmHg with a range of 15– 57mmHg. By assuming a diagnosis of PAH with a RSVP of >40 mmHg, a number of false positive diagnosis will be made. TTE tends to underestimate RVSP in patients with severe PAH and to overestimate RVSP in patients with normal pressures or less severe PAH.
Right ventricle catheterization is considered to be the confirmatory test for PAH diagnosis. Right heart cath tells the severity of haemodynamic changes and test the vasoreactivity of the pulmonary circulation by using short-acting pulmonary vasodilators The high level of anti-U1RNP autoantibodies. The presence of the anti-endothelial cell antibodies, the circulating thrombomodulin and vWFAg may be provoking factors for the development of PAH associated with MCTD. BNP and pro-BNP increases in early disease stages, and correlate well with haemodynamic measures and survival .
EKG: RAD, RVH CXR : prominent pulm artery Pulmonary function testing (PFT): to exclude the underlying airway or parenchymal lung disease. A fall in DLCO with normal lung volumes is suggestive of the early development of pulmonary arterial hypertension Every 6-12 months 6-min walk test: determine disease severity, response to therapy and progression . Its interpretation is limited in MCTD sec to associated co-morbidities. High-resolution CT for interstitial lung disease and V/Q scan for chronic thrombembolic disease.
New York Heart Association functional classificationClass 1 No symptoms with ordinary physical activity.Class 2 Symptoms with ordinary activity. Slight limitation of activity.Class 3 Symptoms with less than ordinary activity. Marked limitation of activity.Class 4 Symptoms with any activity or even at rest.
World Health Organization functional assessment classificationClass I Patients with PH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.Class II Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.Class III Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.Class IV Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.
PAH Immunization against influenza and pneumococcal pneumonia is recommended. Avoid pregnancy; in severe PAH it is recommend to terminate of pregnancy. Avoid estrogen containing OCP; increase risk on thromboembolism Avoid hot bath: peripheral vasodilation and syncope. Laparoscopic procedure with CO2 use for abdominal insufflation, may cause hypercarbia and pulm vasoconstriction.
high altitude Hypoxemia, pulmonary Avoid altitudes 1800 m vasoconstriction supplemental oxygen > 91%Air travel Hypoxemia, pulmonary supplemental oxygen > 91% vasoconstrictionHeavy exertion Near-syncope, syncope Engage in low-level activity or cautious, graduated exercise, such as walkingBending over and rising Near-syncope, syncope Rise slowly from bending, sitting,quickly or lying positionsUse of decongestant Vasoconstriction, worsening consider nonsedatingmedications pulmonary antihistamines or local hypertension treatments, such as nasal steroidsUse of appetite Worsening pulmonary hypertension Have dietary and nutritional,suppressants or diet pills consultation; engage in cautious low-level exerciseHigh sodium intake Fluid retention, right-heart failure Follow 2-g sodium dietCigarette smoking Worsening of intrinsic lung disease; Stop smoking (preferably without Nicotine is a vasoconstrictor use of nicotine replacement therapy)
PAH Supplemental oxygen: sats> 90% Diuretics are indicated for right ventricular volume overload. Digitalis is sometimes used for refractory right ventricular failure Anticoagulation with warfarin is recommended in idiopathic PAH. Anticoagulation is controversial for patients who have PAH due to other causes, such as scleroderma, MCTD or congenital heart disease. NSAIDs and Corticosteroids: improve pulm vascular disease.
Vasodilator Testing and Calcium-Channel Blockers Patients who have a substantial response to a short-acting vasodilator should be considered candidates for treatment with oral calcium-channel blockers Short-acting agents, including intravenous epoprostenol or adenosine and inhaled nitric oxide. Positive response: PAH is a decrease of at least 10 mm Hg in mean pulmonary arterial pressure to 40 mm Hg or less, with increased or unchanged cardiac output. Agents with negative inotropic effects, such as verapamil, should be avoided. Vasodilator response is present in small number of patients with CTD
Prostanoids: vasodilator and antiplatelet. Improve functional capacity and hemodynamic; with no demonstrable survival benefit. Epoprostenol therapy: functional NYHA class III and IV with idiopathic PAH or PAH due to scleroderma/MCTD, it is generally reserved for those with advanced disease refractory to oral therapies. Needs an indwelling central venous catheter. Treprostinil: S/C; NYHA class II, III, IV & when oral therapy fails. Iloprost: Inhalation, NYHA III and IV.
Endothelin-Receptor Antagonists Endothelin-1 is a potent vasoconstrictor and smooth muscle mitogen. Bosentan is approved in the United States for patients with PAH in NYHA class III and IV. S/E : hepatotoxicity, anemia, teratogenicity, testicular atrophy. Response on 6MWD is less in CTD-PAH
Phosphodiesterase-5 Inhibitors Drugs that selectively inhibit cGMP-specific phosphodiesterase augment the pulmonary vascular response to endogenous or inhaled nitric oxide. Sildenafil/Tadalafil has recently been approved by the U.S. Food and Drug Administration for use in PAH.
Combination therapy Combining drugs with different targets is mechanistically appealing because of potential synergy. Sildenafil + intravenous epoprostenol improves exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life. (PACES trail); mainly in IPAH. Sildenafil and bosentan: less efficacy in CTD.
Surgical therapy Atrial septostomy: as a palliative procedure or as a stabilizing bridge to lung transplantation. Lung transplantation.
1.Uwe-Frithjof Haustein. MCTD - Mixed Connective Tissue Disease. JDDG; 2005- 3:97-104 2. Sharp GC, Irwin WS, Tan EM et al. Mixed connective tissue disease: an apparently distinct rheumatic disease syndrome associated with a specific antibody to extractable nuclear antigen. Am J Med 1972 3. PJW Venables. Mixed connective tissue disease. Lupus (2006) 15, 132–137 4. J. Vegh et al; Clinical and Immunoserological Characteristics of Mixed Connective Tissue Disease Associated with Pulmonary Arterial Hypertension. Doi 2006 5. Paul M. Hassoun. Pulmonary Arterial Hypertension 6. Complicating Connective Tissue Diseases. Seminars in respiratory and critical care medicine.2009 7. Lizhi Zhang etal. Pulmonary veno-occlusive disease as a primary cause of pulmonary hypertension in a patient with mixed connective tissue disease. Rheumatol Int (2007) 8. Lewis J. Rubin. Evaluation and Management of the Patient with Pulmonary Arterial Hypertension. 2005 American College of Physicians 9. O. Distler and A. Pignone. Pulmonary arterial hypertension and rheumatic diseases—from diagnosis to treatment. Rheumatology 2006. 10. N Mohan. Importance of screening and early evaluation of pulmonary hypertension and current treatment. J post grad med June 2005. 11. Michael A. Mathier, MD, FACC. The Classification of Pulmonary Arterial Hypertension. Med scape anesthesiology 2006. 12. Faye N etal. Pulmonary manifestation of scleroderma and mixed connective tissue disease.Clin Chest Med 2010.