MIXED CONNECTIVE TISSUE DISEASE WITH PULMONARY FIBROSIS, SECONDARY PULMONARY HYPERTENSION AND HYALINE MEMBRANE DISEASE
Mixed connective tissue disease (MCTD) is an overlap syndrome3,4,5 originally described by Sharp et al in 19721 as an "apparently distinct rheumatic disease syndrome associated with high titers of antibody to an extractable nuclear antigen." It is clinically characterized by features of two or more defined autoimmune diseases, namely systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), dermato- or polymyositis, or rheumatoid arthritis. The initial argument for the existence of this disease entity has been settled by the description of many cases diagnosed by strict clinical criteria2. Further evidence revealed the close association of MCTD with high titers of circulating antibody to a nuclear ribonucleoprotein antigen (anti-U1 RNP), which is a 70-kDa protein complexed to small nuclear RNA. The anti-U1 RNP antibody is highly associated with HLA-DR4. The peak onset of MCTD is in the second and third decades, and women are predominantly affected. The term Overlap syndrome has been used to describe patients who have signs of two or more connective tissue disease simultaneously3,4,5. Some investigators consider MCTD to be an overlap syndrome. The term Undifferentiated connective tissue disease has been suggested as a designation for patients who do not have diagnostic criteria for any one connective tissue disease.
Approximately 85 percent of patients with MCTD have pulmonary involvement, which is often asymptomatic3. Diffusing capacity for carbon monoxide may be the only abnormality. Pleurisy commonly occurs but is seldom associated with large pleural effusions. Some patients develop interstitial lung disease. Pulmonary hypertension (PH) is a common cause of death in MCTD2. A retrospective study of patients with MCTD estimated the incidence of PH to be 4%. PH is usually caused by intimal proliferation and medial hypertrophy of pulmonary arterioles. It resembles the histopathology of primary pulmonary hypertension. The pathophysiology of PH in MCTD is believed to be activation of endothelial cells, with perivascular mononuclear cell infiltrates. The release of angiogenic cytokines is believed to induce vascular damage with proliferative repair, resulting in irreversible proliferative angiopathy. In addition, pericarditis occurs in 30 percent of patients.
The current case had a greater than 10-year history of combined polymyositis, systemic sclerosis with calcinosis, Raynaud's phenomenon, telangiectasis, and high titers of antinuclear autoantibody (ANA) and (+) rheumatoid factor. Two months prior to admission, she developed cardiac tamponade requiring a pericardial window. However, the remainder of her cardiac findings apparently were secondary to the pulmonary hypertension. The ANCA immunofluorescence study at 1:40 dilution was negative. The autopsy revealed multiple systems involved by MCTD characterized by diffuse fibroblast and dense collagen fiber deposition. However, no specific vasculitis was identified except focal perivascular lymphocyte collections involving small vessels in skeletal muscles. There was severe pulmonary interstitial fibrosis which resulted in right sided heart failure. This finding was consistent with her progressive shortness of breath, right ventricle dilatation, and tricuspid and pulmonary regurgitation found three months before death. The hepatomegaly with chronic passive congestion was the consequence of the right sided heart failure.
One striking finding, although not directly related to the cause of death, was the diffuse calcinosis of her soft tissue and skin (Images 01, 02, 03 and 06), especially in sites of previous damage. There are several different forms of cutaneous calcium deposits in MCTD. Among them, metastatic and dystrophic calcifications are most commonly seen. Metastatic calcification occurs in patients with hyperparathyroidism or chronic renal failure, in which the serum calcium-phosphorus product is in the range of 70 to 80. In dystrophic calcinosis cutis, calcium deposits occur in areas of previously abnormal skin in the patients (such as the current case under discussion) with normal serum calcium and phosphorus values7. The local change or disturbance in the tissue, e.g. deposits of abnormal collagen fibers in systemic sclerosis, favors the nucleation of apatite crystals, which initiates the subsequent calcification.8
The postmortem examination also revealed hyaline membrane formation in her right lung. The aerobic culture of peripheral blood harvested during the autopsy revealed Bacillus species. The Bacillus species (B. cereus and subtilis) can occasionally produce infections of the eye, soft tissues, and lung of patients associated with immunosuppression, trauma, indwelling catheter, or contamination of complex equipment such as an artificial kidney6. During the last few days of life, she had fever with leukocytosis and precipitous decline of cardiopulmonary function; it was very likely that she had certain pulmonary infection associated with septicemia. The Bacillus septicemia may have caused the hyaline membrane formation, diffuse alvelar damage. The severe impairment in cardiopulmonary function associated with sepsis are believed to be the immediate causes of her death.
Contributed by Wen-Wei Chung, MD, PhD and Robert E. Lee, MD