The Lung in Mixed Connective Tissue Disease

[Guest guest]

The Lung in Mixed Connective Tissue Disease

E. Girod, M.D., Division of Pulmonary and Critical Care Medicine,

Department of Medicine, University of Texas Southwestern Medical Center, Dallas,

Texas; Marvin I. Schwarz, M.D., Division of Pulmonary Sciences and Critical Care

Medicine, Department of Medicine, University of Colorado Health Sciences Center,

Denver, Colorado

[sem Resp Crit Care Med 20(2):99-108, 1999. © 1999 Thieme Medical Publishers,

Inc.]

Abstract

Mixed Connective Tissue Disease (MCTD) remains a controversial classification

within the field of connective tissue diseases. Since its original description

in 1972 by Sharp et al, different alternative descriptions appear in the

literature, such as " overlap syndrome " or " undifferentiated connective tissue

disease. " The diagnosis is based on the presence of overlapping symptoms of

systemic lupus erythematosus (SLE), systemic sclerosis (SS), and polymyositis

(PM), and the detection of increased titers of anti-RNP (ribonucleoprotein)

antibody. Sharp et al thought that these patients had a distinct rheumatological

syndrome characterized by the absence of arthritis, renal disease, and pulmonary

involvement, as well as a favorable prognosis. Further studies do not support

this benign clinical course that spares the lung. Pulmonary abnormalities have

been described in 25-85% of MCTD patients. The pulmonary manifestations are

similar in presentation and severity as seen in PSS, SLE, and PM. The most

common presentations include interstitial lung disease, pleural effusions, and

pulmonary arterial hypertension. Less common pulmonary presentations are diffuse

alveolar hemorrhage with isolated pulmonary capillaritis, rapidly progressive

pulmonary arterial hypertension, small airway disease, pulmonary embolic

disease, aspiration syndrome, and neuromuscular respiratory failure. The

histologic descriptions of this lung involvement are sparse. Nevertheless, the

need for lung biopsy should be determined on an individual basis and reserved

for atypical presentations. Corticosteroids may be insufficient for the

treatment of MCTD with pulmonary involvement. Early cytotoxic therapy has been

advocated for interstitial lung disease and diffuse alveolar hemorrhage. This

review will present the diagnosis, clinical features, controversies, pulmonary

involvement, therapy, and prognosis of this relatively new disease.

Introduction

The lung is a frequent target of the connective tissue diseases due to its

vascularity and abundant connective tissue.[1] Lung disease associated with

systemic lupus erythematosus (SLE), scleroderma, and polymyositis is frequent.

In 1972, Sharp and colleagues[2] described a novel connective tissue disease,

mixed connective tissue diseases (MCTD).[2] Initial characterization indicated a

relative absence of pulmonary and renal disease, a good prognosis, and

corticosteroid responsiveness. Further experience with MCTD has caused

significant alterations in this concept.[3]

The prevalence of MCTD is unknown. It is believed to occur more commonly than

scleroderma and polymyositis but less than SLE. MCTD is defined by the presence

of clinical features of SLE, progressive systemic scelerosis (PSS), and

polymyositis (PM) and high titers of an antinuclear antibody specific for a

nuclear riboprotein (RNP). This antigen was initially identified as an

extractable and RNAse-sensitive nuclear antigen (ENA).[4]

Recent evidence indicates a high incidence of pulmonary disease in MCTD.[5]

Reports of rapidly progressive pulmonary hypertension, pulmonary fibrosis, and

isolated pulmonary capillaritis with alveolar hemorrhage are increasing.

This review will focus on MCTD, its controversial classification, and its

presentation. Moreover, the pulmonary manifestations will be emphasized.

Mixed Connective Tissue Disease

Controversial Classification

The classification of a connective tissue depends on the presence of identifying

clinical features, characteristic laboratory tests, and specific antibodies.

Prior to the description of MCTD,2 patients were recognized who exhibited

features of more than one connective tissue disease. In fact, up to 25% of

patients with a connective tissue disease fell into this category.[6] Terms such

as " overlap syndrome, " " sclerodermatomyositis, " and " undifferentiated connective

tissue disease " have been ascribed to such patients.[4]

Sharp et al[2] demonstrated patients with " overlap " features and a specific

antibody to RNP (ribonucleoprotein). These patients had relative sparing of the

kidneys and lung and a favorable response to corticosteroid medication. In 1980,

Nimelstein et al[7] performed a follow-up study of the patients originally

described by Sharp and colleagues. Of 17 patients available, 10 were diagnosed

as having PSS. Several did not have the expected response to corticosteroids

thus requiring high doses of prednisone. In addition, the presence and titer of

the anti-RNP antibody was not persistent nor did it correlate with the clinical

symptoms.

Further evidence against the existence of MCTD as a distinct entity is the

description of significant visceral organ involvement. This damage is frequently

progressive and corticosteroid resistant. Renal involvement, initially thought

not to occur, has been found in 10 to 30% of MCTD patients.[4] Severe

neuropsychiatric illness, carditis, pericarditis, and deforming arthritis are

also being described. Pulmonary disease will be discussed in detail below.

Three sets of diagnostic criteria have been put forth.[8-10] Two list the

anti-RNP antibody as an essential component. Lázaro and colleagues[11] studied

clinical and serological criteria in 27 patients with " overlap syndrome. " They

found that the presence of the anti-RNP antibody did not identify a distinct or

separate group of patients. Also, if clinical criteria are utilized for the

diagnosis of MCTD, the predictive value of the anti-RNP antibody falls to as low

as 38-69%.[12]

Controversy still exists concerning MCTD being a separate connective tissue

disease.[11] Many experts have compared MCTD to a " tropical storm, " [13] with

patients starting their clinical course in the " eye of the storm " without a

defined connective tissue disease. As the syndrome or " storm " progresses, these

patients develop more characteristic criteria for a conventional or definite

connective tissue disease.[14] Many prefer the term " undifferentiated connective

tissue disease " or " overlap syndrome. " [3] Nevertheless, rheumatology textbooks

recognize MCTD as a separate entity within the rheumatological diseases.[15]

General Presentation of MCTD

The prevalence of MCTD is thought to be higher than progressive systemic

sclerosis and polymyositis and less than SLE.5 There is a marked predominance of

women over men (15:1).[16] Age at presentation ranges from 5-80 years with a

mean of 37.16 Studies of families with MCTD have demonstrated no clear inherited

pattern or genetic predisposition.[17] An increased frequency of HLA-DR4 Dw4

subtype has been detected in a subset of patients.[18]

The hallmark of this disease is the presence of features of SLE, PSS, and PM, as

described in other research. Three quarters of patients have swollen hands,

sclerodactyly, dyspnea, Raynaud phenomenon, esophageal dysmotility, myositis,

and arthralgias (Table 1),[19,20] although the arthritis is usually

polyarticular and nondeforming, an erosive arthritis resembling rheumatoid

arthritis has been reported.[19]

Renal disease occurs in approximately 10-20% of patients and necessitates

corticosteroid or cytotoxic therapy.[4] Renal biopsies most often demonstrate

membranous glomerulonephritis.[20] A review of 13 MCTD cases with immune-complex

glomerulonephritis (GN) lists the following histological features: membranous GN

(9 patients), focal mesangial GN, diffuse proliferative GN,

membranoproliferative GN, and tubulointerstitial nephritis.[21] One patient

diagnosed with MCTD developed a picture consistent with scleroderma renal

crisis. Kidney biopsy demonstrated endothelial cell proliferation and luminal

thrombosis of small arteries.[22]

Cardiac disease is found in those MCTD patients with predominant SLE features.

Pericarditis is the most common abnormality. A chest pain syndrome can develop

in association with intimal proliferation and leukocytic perivascular

infiltration of the intra-myocardial arteries. Autopsy studies have also

demonstrated focal cardiac fibrosis.[19]

Neuropsychiatric illness was not considered a component of the original MCTD

description.[2] Further studies describe 11 of 20 MCTD patients affected by a

neuropsychiatric illness.[23] The most common presentation is aseptic meningitis

with cerebrospinal fluid pleocytosis and elevated protein. Other reported

neurological manifestations include grand mal seizures, trigeminal neuralgia,

and a sensory polyneuropathy. Psychosis and paranoid delusions are the most

common psychiatric illnesses described.

Immunological Studies

MCTD is characterized by a high titer of the anti nuclear antibody (ANA) in a

speckled pattern.[24] This pattern is secondary to high titer (1:10,000 or

1:100,000) antibody to a nuclear ribonucleoprotein (anti-RNP), which is an ENA.

The presence of this antibody is considered essential for the diagnosis of

MCTD.[16] The epitope for the anti-RNP antibody has been identified to be three

nuclear proteins (70K, A, and C) that associate exclusively with a small nuclear

RNA molecule, U1RNA. Another extractable nuclear antigen related to the RNP is

the SM antigen, which is characteristic of SLE. This antigen, in contrast with

the RNP antigen, is resistant to RNAse digestion.[13] Characteristically, MCTD

patients have absent antibodies to the Sm antigen again supporting a distinct

rheumatological entity.[5]

The anti-RNP antibody and its relationship to disease activity have been studied

with conflicting opinions.[13] Lázaro et al.[11] reported the lack of

correlation between a high RNP titer and disease presentation and severity. In

contrast, Sullivan et al[19] describe an association of low anti-RNP titers and

remission or at least mild disease. Four deaths were seen in patients with

persistently elevated anti-RNP titers.

Other laboratory markers include elevated sedimentation rates, rheumatoid factor

(>50%), LE preparations (16%),[2] and mild decrease in complement levels

(25%).[16]

MCTD and the Lung

Overview

Pulmonary manifestations were not originally described by Sharp and

colleagues.[2] Further studies of MCTD highlight the lung as a common target

organ in 25-85% of patients.[25] A prospective study of 28 patients demonstrated

that 80% of these patients had evidence for pulmonary disease, however, 69% of

them were asymptomatic.[19] The lung manifestations resemble those of PSS, SLE,

and PM.[26]

Symptoms are dyspnea, cough, and chest pain or tightness. The pulmonary disease

can have an insidious onset. Approximately 80% of MCTD patients can present with

abnormal chest radiographs and pulmonary function tests (PFTs) despite being

asymptomatic.[4,5] Physical examination may reveal crackles, increased pulmonic

valve closing sound (P2), or signs consistent with a pleural effusion.

Scleroderma-like skin changes in association with abnormal nail fold capillaries

have been associated with the presence of pulmonary arterial hypertension.[19]

Table 1 summarizes some of the clinical findings of MCTD patients.

The chest radiograph in MCTD patients with pulmonary involvement shows a variety

of patterns: bibasilar and patchy interstitial infiltrates, pleural effusion,

pleural thickening, nonspecific pneumonitis, and segmental atelectasis.[5] A

pattern of bilateral alveolar infiltrates has been described in association with

diffuse alveolar hemorrhage and capillaritis[27] or an infectious process.

Pulmonary function testing demonstrates abnormalities in 70% of MCTD

patients.[5] Sullivan et al[19] prospectively studied 34 MCTD patients. A

significant reduction (<75% of predicted) in diffusing capacity for carbon

monoxide (DLCO) (72% patients), forced vital capacity (34%), and resting

hypoxemia (21%) was observed. A retrospective review demonstrated a restrictive

physiology in 69% of patients tested.[5] A characteristic finding was a low DLCO

(20-66% of predicted). Derderian and colleagues,[24] in a study of 13 patients,

demonstrated that 62% of patients had lung volumes that were less than 80%

predicted. All studies suggest that the measurement of DLCO might serve as the

most sensitive marker of pulmonary involvement in MCTD. Table 2 lists the

described pulmonary manifestations of MCTD.

Interstitial Lung Disease (ILD)

ILD is either the first or second most common pulmonary complication of MCTD.

Chest radiographic or PFTs abnormalities consistent with an interstitial process

are observed in 21-85% of MCTD patients.[5,19] The clinical picture consists of

dyspnea, restrictive pulmonary physiology, a reduced DLCO, and an abnormal chest

radiograph with patchy bibasilar reticular infiltrates. The pulmonary

infiltrates first present at the periphery of the lung bases and progress to

involve the apices.[5] Honeycombing is seen with advanced disease particularly

in those MCTD patients with a predominant PSS picture[4] (Fig. 1A and .

The underlying histology of the interstitial process is not well defined. When

described, the histology is similar or identical to that seen in idiopathic

pulmonary fibrosis or scleroderma-associated ILD (usual interstitial

pneumonitis). In most cases, the diagnosis is based on clinical grounds and the

patients are empirically treated with corticosteroids.

Wiener-Kronish et al[28] described two patients with pulmonary fibrosis as

suggested by chest radiographs and pulmonary function tests. One patient, a

37-year-old man, had a transbronchial biopsy demonstrating moderate interstitial

fibrosis, alveolar epithelial cell hyperplasia, and interstitial infiltration

with plasma cells and lymphocytes. This patient's pulmonary disease progressed

and led to his death despite corticosteroid and cyclophosphamide therapy. In

another, open lung biopsy indicated a more advanced interstitial fibrosis with

honeycomb changes that progressed despite prednisone and chlorambucil treatment.

In contrast, Takeda[29] reported a case of a 43-year-old woman with MCTD and

rapidly developing interstitial infiltrates who responded to pulse

glucocorticoid therapy (methylprednisolone 1g/day for 3 days). Suzuki and

colleagues30 reported a case of a 55-year-old man with rapidly declining

pulmonary function and interstitial fibrosis who failed to respond to

corticosteroids but improved on azathioprine therapy.

An interesting feature of the anti-RNP antibody is high frequency of positivity

(even at high titers) in patients with idiopathic pulmonary fibrosis but without

other features of MCTD. Chapman et al[31] studied 122 patients with idiopathic

pulmonary fibrosis (cryptogenic fibrosing alveolitis) without evidence of MCTD

and demonstrated that 12% of patients had positive titers to anti-RNP antibody.

Pleural Effusion

Pleural effusion in MCTD usually occurs in patients with predominant SLE

features.[4] Pleuritic chest pain can be the presenting pulmonary complaint. The

frequency of pleural effusions in MCTD patients ranges from 2 to 6%. The

effusions are either right-sided or bilateral.[5,14] They are usually small and

therefore not sampled for diagnostic purposes. When sampled, they are exudative.

They are usually self-limited or respond to corticosteroid therapy. Pleural

loculations, organization, or fibrothorax have not been reported.

There are only three reports of thoracentesis being performed in MCTD-associated

pleural effusions. In one, it was described as straw-colored fluid with a normal

glucose, total protein of 3.8 g/dL and normal complement levels.[5] Hoogsteden

et al[32] reported an unusual case of an 18-year-old woman whose initial

presentation with MCTD consisted of large bilateral exudative pleural effusions.

She presented with fever, pleuritic chest pain, and dyspnea. Her pulmonary

function tests revealed a restrictive pattern and a normal DLCO. The pleural

fluid analysis revealed a total protein of 4.2 g/dL, normal pH, and an increased

LDH (411 IU/L). Pleural fluid cell and differential counts revealed a

predominance of neutrophils corroborated by monoclonal antibody testing of cell

surface markers. This patient's effusions resolved without corticosteroid

therapy. Another initial presentation of MCTD with a left pleural effusion was

described in a 79-year-old man.[33] Thoracentesis revealed an exudate with

lymphocytosis. Pleural biopsy revealed a lymphoplasmocytic pleuritis. Resolution

with prednisone (40 mg/day) occurred.

Pulmonary Arterial Hypertension (PAH)

Pulmonary arterial hypertension (PAH) is less frequently seen than interstitial

lung disease. Nevertheless, PAH is considered the more serious complication

because it is characterized by rapidly fatal course.[4,25,34] Of note,

progressive pulmonary hypertension is usually limited to MCTD patients with

predominantly scleroderma-like features.[19] Possible mechanisms of the

pulmonary arterial hypertension development in MCTD include vasoconstriction

secondary to pulmonary fibrosis, thromboembolic disease,[21] or a plexogenic

arteriopathy, similar to that observed in progressive systemic sclerosis and

primary pulmonary hypertension.[4]

The usual presentation is exertional dyspnea and fatigue. Physical examination

may reveal a loud pulmonic second heart sound, described prospectively in 27% of

a general survey of 34 MCTD patients. The chest radiograph can be normal or have

interstitial infiltrates, or show evidence of central pulmonary artery

enlargement. Characteristically, these patients have a progressive decline of

the DLCO.[25]

Ozawa and colleagues35 found a correlation between angiotensin I-converting

enzyme (ACE) levels and PAH in MCTD. They observed that ACE levels greater that

28.3 mU/ml differentiated MCTD patients with PAH from those without pulmonary

hypertension. This was documented in four of six MCTD patients with PAH and in

none of the patients without PAH.

The pathology of pulmonary hypertension is similar to that seen in

scleroderma-associated pulmonary hypertension (Fig. 2). It is characterized by

profound intimal and medial hypertrophy of small and medium-sized arteries,

disordered array of collagen fibers, plexiform lesions, obliteration of the

arterial lumen, and intimal fibrosis of pulmonary veins.[4,19] These lesions are

usually associated with fibroblastic proliferation and increased collagen

deposition, specifically type III collagen.[36]

The association of scleroderma-like features in MCTD and the development of PAH

has been strengthened by studies of peripheral capillaries utilizing nail bed

capillary microscopy. In Sullivan's[19] prospective study, 11 patients underwent

nail bed capillary microscopy with 6 patients yielding abnormal results. These

six presented with or developed pulmonary arterial hypertension during

follow-up. Of note, no patient with normal capillary microscopy developed

pulmonary hypertension.

Wiener-Kronish and colleagues[28] described three MCTD cases with pulmonary

arterial hypertension. One, a 21-year-old woman, had a rapidly progressive

picture with cardio-respiratory arrest. Autopsy demonstrated not only a picture

consistent with a plexogenic arteriopathy, but also an acute, necrotizing

vasculitis with IgG granular deposits in the lungs and kidney.

Diffuse Alveolar Hemorrhage and Pulmonary Capillaritis

Diffuse alveolar hemorrhage and pulmonary capillaritis occurs most frequently in

SLE but rarely in MCTD patients. Pulmonary capillaritis is characterized by a

necrotizing neutrophilic small vessel vasculitis and interstitial pneumonitis.

The resultant destruction of alveolar capillary structure leads to red blood

cell leakage into the alveolar space. The interstitium is infiltrated by

neutrophils, many undergoing fragmentation causing a characteristic accumulation

of nuclear debris. The interstitium becomes edematous and undergoes fibrinoid

necrosis[27] (Fig. 3).

DAH is characterized by anemia, hemoptysis (not always present), hypoxia, acute

respiratory failure, and bilateral pulmonary infiltrates (Fig. 4). This

potentially lethal syndrome requires rapid diagnostic evaluation and

intervention.[37] Reports of this syndrome in MCTD are limited to individual

cases.

-Guerrero and colleagues[37] reported a 30-year-old woman who presented

with arthralgias, digital ulcers, myopathy, esophageal dysmotility, xerostomia,

and skin changes. She had significant dyspnea and restrictive pulmonary

function. While being treated with prednisone 60 mg/day, she developed acute

respiratory failure and bilateral alveolar infiltrates. Autopsy revealed a renal

vasculitis with IgM and complement immune deposits by immunofluorescence. Lung

examination confirmed diffuse alveolar hemorrhage, but pulmonary vasculitis or

capillaritis was not described.

Germain and colleagues[20] described a 37-year-old woman with a long-standing

history of MCTD and a membranous nephropathy. She developed acute decompensation

with hemoptysis, dyspnea, and bilateral pulmonary infiltrates. Lung biopsy was

not performed and diagnosis of DAH was made clinically. She was successfully

treated with pulse intravenous methylprednisolone therapy and a short course of

cyclophosphamide.

The prior reports describe a bland diffuse alveolar hemorrhage without active

necrotizing pulmonary vasculitis. In contrast, Schwarz and colleagues[27]

described the first case of diffuse alveolar hemorrhage with isolated pulmonary

capillaritis in MCTD. This patient did not have an active glomerulonephritis.

This 45-year-old woman presented in acute respiratory failure requiring

intubation and mechanical ventilation. Biopsy of the lung revealed immune

deposits consisting of IgG and complement suggesting an etiological role for

immune complex formation. The patient was successfully treated with high-dose

methylprednisolone (1 g/day in divided doses) and intravenous cyclophosphamide

(1 gm/m2).

Pulmonary Aspiration Syndrome

Esophageal dysmotility is common in MCTD patients. The reported incidence of

abnormal barium esophagograms and manometry is 53 and 69%, respectively.

Abnormalities of esophageal manometry resemble those of PSS and include

aperistalsis and hypotonicity of the lower esophageal sphincter. This

potentially is associated with chronic reflux and risk of aspiration

pneumonitis.[4]

In patients with MCTD and pulmonary disease, the incidence of esophageal

involvement is 80%. The possibility that chronic aspiration may contribute to

pulmonary fibrosis has not been confirmed.[5] Death secondary to

aspiration-induced adult respiratory distress syndrome has been described.[5]

Miscellaneous Presentations

Because MCTD has features of PSS, SLE, and polymyositis, the literature includes

many case reports of unusual pulmonary presentations. Pulmonary nodules,

diaphragmatic muscle weakness, mediastinal adenopathy, concomitant sarcoidosis,

and small airway disease have been described.

Pulmonary nodules were seen in a patient with presumed MCTD (anti-RNP antibody

high titer 1:102,400).[38] These pulmonary nodules cavitated and were thought to

represent a pulmonary vasculitis, although tissue was not obtained. In Webb's

series,[38] the SLE patients with cavitary nodules did not have vasculitis, but

either underlying infection (bacterial, Aspergillus, or tuberculosis) or

pulmonary thromboembolus. Therefore, a search for an infectious or embolic

etiology is recommended in the evaluation of pulmonary nodules in MCTD and other

rheumatological diseases.

Inflammatory myositis was reported in 79% of the 34 patients reported by

Sullivan et al.[19] However, chronic respiratory failure or diaphragmatic

dysfunction was not mentioned.[19] Two case reports describe respiratory

failure[39] and diaphragmatic dysfunction[40] in patients with MCTD.

Mediastinal adenopathy has been described in two MCTD patients. Mediastinal

lymph node biopsies demonstrated a nonspecific lymphoid reaction without

granulomas or other abnormalities.[4] Mizumoto et al[41] describe a 61-year-old

woman with cervical and mediastinal adenopathy and bibasilar reticulonodular

infiltrates. There were clinical features of an overlap syndrome with a positive

anti-RNP antibody and absence of anti-Sm, anti Jo-1, and anti-DS DNA antibodies.

A diagnosis of MCTD was made. Bronchoscopy with transbronchial biopsies

demonstrated pulmonary granulomas. Although granulomas are rarely described in

SLE and PSS, a diagnosis of co-existent MCTD and sarcoidosis was made.

Primary obstructive lung disease (bronchiolitis obliterans) has not been

described in MCTD. In 1993, Izumiyama[42] and colleagues performed pulmonary

function tests in 17 female patients with MCTD but without cardiac or pulmonary

symptoms. This included the assessment of small airway involvement by estimation

of the frequency dependence of dynamic compliance. This study was based on the

fact that early interstitial pneumonia, commonly seen in asymptomatic patients

with MCTD, can be associated with inflammation of the small airways

(bronchiolitis). All patients had abnormal frequency-dependent dynamic

compliance. A decrease in vital capacity and DLCO was observed only in 35 and

47% of patients, respectively. These patients were followed for a maximum of 5

years but histology was not available. A correlation with the development of

pulmonary disease correlated with the serial DLCO measurements. Nevertheless,

this study suggests that involvement of small airways might be a frequent and

early manifestation of MCTD and likely represents ongoing interstitial

inflammation.

Diagnosis of Pulmonary Involvement

Because open lung biopsy findings rarely influence therapy, it is recommended

that MCTD patients with suspected pulmonary involvement undergo noninvasive

testing. In most cases, this evaluation will clearly distinguish whether the

dyspnea is due to cardiac disease, pulmonary arterial hypertension, aspiration

syndrome, interstitial lung disease, or infection. If clinical, radiological,

and physiological studies do not suggest an etiology for the patients'

presentation, occult thromboembolic disease, cardiac disease, or pulmonary

arterial hypertension should be considered and these patients should undergo

cardiac catheterization or pulmonary angiography.

Bronchoscopy with or without biopsies and bronchoalveolar lavage should be

performed for the diagnosis of infectious complications, especially in

immunosuppressed patients, and to document diffuse alveolar hemorrhage by serial

bronchoalveolar lavage, if clinically suspected. If a patient is suspected of

having an interstitial lung disease, open lung biopsy should be reserved for

atypical presentations such as unexplained bilateral alveolar opacities,

suspicion of opportunistic infection with negative bronchoscopy, or unexplained

adult respiratory distress syndrome (ARDS).

Therapy and Prognosis

MCTD was originally thought to be a distinct rheumatological entity with a

favorable prognosis that responded to low-dose corticosteroid medication.[2,13]

Black and Isenberg[13] reviewed 194 patients and noted that 13% were dead within

12 years of diagnosis. Other studies demonstrate that internal organ involvement

is common and require higher doses of corticosteroids or cytotoxic therapy.[28]

Studies demonstrate that corticosteroid therapy is more effective for pleural

disease and other acute inflammatory processes. Sclerodactyly, scleroderma skin

changes, esophageal dysmotility, and interstitial pulmonary disease are less

responsive.[19] Treatment with prednisone or cytotoxic agents should be

considered for patients with renal and pulmonary involvement or those with

symptomatic myositis, arthritis, or systemic illness that does not respond to

prednisone alone.[43]

The guidelines for treatment of the pulmonary complications observed in MCTD

come from anecdotal experience.[2,5,19,24,28] Wiener-Kronish et al28 described

five patients with either progressive pulmonary arterial hypertension or

interstitial lung disease. None improved with corticosteroid therapy alone. On

the other hand, two patients with interstitial lung disease responded to

chlorambucil (8 mg/day). In another prospective study,19 33 of the 34 MCTD

patients required treatment with corticosteroids. Twelve had severe and

progressive systemic disease requiring the addition of cyclophosphamide therapy.

Seven stabilized or improved on this therapy. In another series, 20 out of 81

patients had pulmonary involvement.5 Only eight patients received prednisone at

doses ranging from 5-60 mg/day. Two patients had resolution of symptoms and

radiographic abnormalities, but the rest had no improvement or deterioration.

Further studies in MCTD are necessary to provide clearer therapeutic guidelines.

The studies listed above suggest that the pulmonary disease in MCTD can be

progressive and relatively corticosteroid resistant. Therefore, early addition

of cytotoxic therapy in patients with progressing interstitial pulmonary

fibrosis or pulmonary arterial hypertension should be considered.

Conclusion

In the last 26 years, studies have presented clinical and scientific evidence

that both agrees and disagrees with its classification as a distinct

rheumatological entity. Pulmonary involvement is more frequent than originally

thought and is a frequent cause of death. Pleural effusions, interstitial lung

disease, and PAH are the most common presentations. The diagnosis of MCTD lung

involvement can usually be established by noninvasive testing. Lung biopsy is

not recommended unless uncharacteristic pulmonary presentation or infectious

complication is suspected. Anecdotal reports suggest a poor response to

corticosteroids and the need for cytotoxic therapy. Further clinical studies are

required to clarify many of the controversies and possible therapeutic

interventions of this relatively young disease.

Supported by National Heart, Lung, and Blood SCOR Institute Grant, HL27353.

Reprint requests: Dr. Girod, Division of Pulmonary and Critical Care Medicine,

University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas,

TX 75235-9034

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