Mixed Connective Tissue Disease: The Spectrum of Radiographic Manifestations 1
Diagnostic Radiology
Eric J. Udoff, M.D., Harry K. Genant, M.D., Franklin Kozin, M.D., and Mark Ginsberg, M.D.
Mixed connective tissue disease (MCTD) is a serologically distinctentity defined by a ribonuclease-sensitive extractable nuclear antigen. This unusual overlap syndrome hasclinical features of scleroderma, systemic lupus erythematosus, polymyositis, andrheumatoid arthritis. In orderto definethe radiographic changes in MCTD, radiographs of the hands of 17 patients werestudied, utilizing a fine-detail technique. Diffuse and periarticular osteopenia were found in 8 and 10 patients, respectively; soft-tissue swelling in 11; erosive changes in 9; joint-space narrowing in 7; tuft resorption and soft-tissue atrophy in 6; and subluxations in 2. In individual cases radiographs may appear normal or exhibit features of scleroderma, systemic lupus erythematosus or rheumatoid arthritis, thereby mirroring the clinicaldiversity of this entity. INDEX TERMS: Arthritis, rheumatoid. Connective tissue • Lupus erythematosus • Mixed connective tissue disease (MCTD) • Myositis ossificans • Sclerdoderma • (Wrist and hand, other connective tissue disorder 4[3] .619) • (Wrist and hand, rheumatoid arthritis 4[3] .711) Radiology 124:613-618, September 1977
RESULTS
IXED CONNECTIVE TISSUE DISEASE (MCTD) is a distinct overlap syndrome combining features of scleroderma, systemic lupus erythematosus, polyrnyosltls, and rheumatoid arthritis (10-15). Patients with the MCTD possess an antinuclear antibody, characterized by its reaction with a ribonuclease-sensitive extractable nuclear antigen (ENA) (14, 15). In the present study the radiographic manifestations of 17 patients with the MCTD are reviewed, and the clinical diversity of the syndrome is discussed.
M
The clinical and laboratory findings are summarized in TABLE I, and the fine-detail radiographic analysis is presented in TABLE II. A total of 32 joints was examined per patient (8 distal interphalangeal (DIP), 10 proximal interphalangeal (PIP), 10 metacarpophalangeal (MCP), 2 carpo-metacarpal joints of the thumbs, and the carpal and wrist joints of each hand taken as one). Swelling was present in the DIP joints of 2 patients, PIP joints of 8 patients (Fig. 1, B), MCP joints of 3, and wrists of 3 (Fig. 4, A). Ten of 17 patients (59%) had definite (Grade 2 or 3) periarticular osteopenia (Figs. 1, A; 2, A; and 3, A), and 8 had diffuse osteopenia. Joint-space narrowing was noted in 7 patients (41 %), involving the DIP [ 1], PIP [6], MCP [1], and wrist [1] (Fig. 3, C) joints. Nine patients exhibited definite erosive lesions; these were located in the DIP [4] (Fig. 2, B), PIP [9] (Figs. 1, B; 4, B; 6, B; and 6, C), MCP [5] (Fig. 3, C), wrist or carpal joints [6] (Fig. 3, A and B), and ulnar styloid [3] (Fig. 4, A). Resorption of the distal phalangeal tuft was found in 6 patients (Fig. 5), and 6 had soft-tissue atrophy over the distal phalanx (Fig. 1, A). A sequential study of fine-detail radiographs was available for patient A.E. Over a 21-month interval (January 1973 to September 1974) there was progression from minimal (Grade 1) to definite (Grade 2) erosions in the MCP joints and from minimal to deeper pocketed (Grade 3) erosions in the DIP and PIP joints (Fig. 6, B and C). Three of 5 seropositive (rheumatoid factor) patients had erosive lesions. There were 6 additional patients with erosive disease, representing 36 % of the seronegative group.
MATERIALS AND METHODS
Fourteen women and 3 men with MCTD were studied. They ranged in age from 18 to 63 years (mean 38.6 years) and the duration of symptoms prior to study was 1-24 years (mean 7 years). The clinical and serologic findings in this group were similar to those described for MeTD (TABLE I). All patients had a positive antinuclear antibody test and hemagglutinating antibodies to the ribonuclease-sensitive ENA, termed ribonucleoprotein (10-15).2 Patients with anti-Sm antibodies were excluded from the study as this is thought to be present primarily in systemic lupus erythematosus (SLE) (10). Rheumatoid factor was measured by a standard latex fixation method. Radiographs of the hands of all patients were obtained with a fine-detail, non-screen technique with Kodak Type M film as previously described (1, 4, 6-9). Radiographs were processed and examined at four to eightfold optical magnification (8, 9). These were graded for diffuse and periarticular osteopenia, soft-tissue swelling, joint-space narrowing, and bony erosion according to the following scale (9): 0 (none), 1 (borderline), 2 (definite), and 3 (severe).
1 From the Departments of Radiology of The University of Chicago Hospitals and Clinics (E.J.U., ChiefResident) and the University of California Medical Center at San Francisco (H.K.G., Associate Professor of Radiology), and the Departments of Medicine of the Medical College of Wisconsin (F.K., Assistant Professor of Medicine) andthe University of California at San Diego(M.G., Assistant Professor of Medicine). Revised manuscript accepted for publication in February 1977. 2 These studies were kindly performed by Dr. Gordon C. Sharp, University of Missouri Medical School, Columbia, Missouri, or Dr. EngM. Tan, Scripps Clinic & Research Foundation, La Jolla, California. shan
613
614
ERIC
J.
UDOFF AND OTHERS
September 1977
Fig. 1. A and B. Moderate juxta-articular demineralization associated with periarticular soft-tissue swelling and abnormal tapering of the distal soft tissues (A). Close-up view of proximal interphalangeal joint of this patient (8) demonstrates capsular distension and early surface erosion of the phalangeal condyle (arrows).
DISCUSSION
Connective tissue overlap syndromes in which features of several distinct diseases are present have been studied previously (2, 3, 16). The group described here with mixed connective tissue disease (MCTD) is unique in that it is associated with a specific antinuclear antibody directed at a saline extractable antigen, ribonucleoprotein (10-15). Clinically, the MCTD is characterized by features of scleroderma (Raynaud's phenomenon, skin changes, dysphagia), systemic lupus erythematosus (skin rash, serositis, fevers, lymphadenopathy), polymyositis, and rheumatoid arthritis (15). It appears to be an important subgroup of the "collagen vascular" diseases in that there is a lower incidence of serious renal involvement and a more predictable response to corticosteroid therapy (14, 15). The radiographic characteristics of the MCTD have not been examined systematically as yet, although a recent report of 3 cases demonstrated a variety of joint and soft-tissue changes (16). In our group of 17 patients studied by the technique of fine-detail radiography, the pattern of joint disease was diverse, mimicking the clinical diversity of the syndrome. Features of scleroderma (tuft resorption and DIP erosions), rheumatoid arthritis (erosive arthritis),
and systemic lupus erythematosus (deforming, nonerosive arthritis) were apparent. Radiographs of one patient demonstrated progressive erosive disease. Several patients had entirely normal radiographs. Of interest was the observation that 36 % of seronegative patients exhibited bony erosions. It is possible that this represented scleroderma joint disease in 2 patients (S.8., F.P.), as there was associated distal tuft resorption; it is also possible that patients with the MCTD constitute a subgroup of so-called seronegative rheumatoid arthritis. The results presented here must be interpreted with caution in view of the highly selected nature and relatively small group of patients. However, it is important that the radiologist recognize this newly described, serologically distinct connective tissue syndrome, mixed connective tissue disease, in which the clinical diversity is reflected by the radiographic diversity.
Eric J. Udoff, M.D. Department of Radiology University of Chicago 950 East 59th Street Chicago, III. 60637
Diagnostic Radiology
Fig. 2. A and B. Striking subluxation of interphalangeal joint of the thumb and advanced ulnar deviation with subluxation of the second through fifth metacarpophalangeal joints (A). Moderate juxta-articular demineralization is also demonstrated. Close-up view of distal interphalangeal joint of this patient (B) shows surface erosion and crumbling of subchondral bone.
Fig. 3. A-C. Juxta-articular demineralization and erosive articular disease (A). Close-up view of the wrist (B) shows near-total loss of cartilage in the carpal and radiocarpal joints associated with erosive articular disease. Ulnar drift of the carpus is also demonstrated. Close-up of the MCP joints (C) demonstrates joint narrowing, erosive articular disease and mild reactive sclerosis of the second MCP joint.
615
Fig. 4. A and 8. Close-up view of ulnar styloid demonstrating pocketed erosion and overlying soft-tissue swelling. Proximal interphalangeal joint of this patient (8) shows similar erosive articular disease of the condyles.
Fig. 5. Resorption of a portion of the distal phalangeal tuft is shown.
Fig. 6. A-C. Subtle surface erosions (closed arrows) of the metacarpal head and base of proximal phalanx simulating early rheumatoid arthritis (A). In (8) and (C) progressive erosions (open arrows) of the proximal interphalangeal joint can be seen occurring over a 21-month period.
616
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24-F
53-F
39-F
15. FG
16. KH
17. I
18.0
1
2
2
2
6 6 12
3
81,920 16,000
320
10,240 2,560 2,560 80 20,480
AntiRNp 2
100,000 ( 10) 10,000 ( 0) 10,000 ( 0) 10,000 ( 0) 100,000 ( 10)
100,000 (10) 100,000 (10)
Pos
6
Pos" Pos"
AntiENA 3
-
+
-
-
-
+
-
-
-
+
+ + +
+ + +
+
+
-
+ + +
+
+
-
-
+
+
-
+
+ +
-
-
+
-
+
+ + +
+
+
-
+ +
-
+
-
+ + + + +
+ + +
-
+
+
+ -
+ + +
Raynaud's Hand Phenom- Swelling enon
-
RF 4
Arthritis
Clinical Findings
+
0
+
-
-
+
0
0
+
-
+
-
-
-
-
+
-
-
-
-
+
-
+
+ +
0 0
-
0 + + +
7/18
+
+
+
+
+ + +
Abnormal Abnormal PulPolyEsoph- monary myositis ageal Func(Muscle Motility tion Biopsy)
15/18 16/18 12/18 8/14 5/16 1+ = Present; - = absent; 0 = not tested. 2Anti-RNP antibodies expressed as reciprocal titer (performed by Dr. Eng M. Tan). 3Anti-ENA antibodies before and after (in parenthesis) ribonuclease digestion (performed by Dr. Gordon Sharp). "Rheumatoid factor as reciprocal titers by sensitized sheep cell or latex fixation tests; positive = titer> 180. STotal WBC count
Diagnostic Radiology
Eric J. Udoff, M.D., Harry K. Genant, M.D., Franklin Kozin, M.D., and Mark Ginsberg, M.D.
Mixed connective tissue disease (MCTD) is a serologically distinctentity defined by a ribonuclease-sensitive extractable nuclear antigen. This unusual overlap syndrome hasclinical features of scleroderma, systemic lupus erythematosus, polymyositis, andrheumatoid arthritis. In orderto definethe radiographic changes in MCTD, radiographs of the hands of 17 patients werestudied, utilizing a fine-detail technique. Diffuse and periarticular osteopenia were found in 8 and 10 patients, respectively; soft-tissue swelling in 11; erosive changes in 9; joint-space narrowing in 7; tuft resorption and soft-tissue atrophy in 6; and subluxations in 2. In individual cases radiographs may appear normal or exhibit features of scleroderma, systemic lupus erythematosus or rheumatoid arthritis, thereby mirroring the clinicaldiversity of this entity. INDEX TERMS: Arthritis, rheumatoid. Connective tissue • Lupus erythematosus • Mixed connective tissue disease (MCTD) • Myositis ossificans • Sclerdoderma • (Wrist and hand, other connective tissue disorder 4[3] .619) • (Wrist and hand, rheumatoid arthritis 4[3] .711) Radiology 124:613-618, September 1977
RESULTS
IXED CONNECTIVE TISSUE DISEASE (MCTD) is a distinct overlap syndrome combining features of scleroderma, systemic lupus erythematosus, polyrnyosltls, and rheumatoid arthritis (10-15). Patients with the MCTD possess an antinuclear antibody, characterized by its reaction with a ribonuclease-sensitive extractable nuclear antigen (ENA) (14, 15). In the present study the radiographic manifestations of 17 patients with the MCTD are reviewed, and the clinical diversity of the syndrome is discussed.
M
The clinical and laboratory findings are summarized in TABLE I, and the fine-detail radiographic analysis is presented in TABLE II. A total of 32 joints was examined per patient (8 distal interphalangeal (DIP), 10 proximal interphalangeal (PIP), 10 metacarpophalangeal (MCP), 2 carpo-metacarpal joints of the thumbs, and the carpal and wrist joints of each hand taken as one). Swelling was present in the DIP joints of 2 patients, PIP joints of 8 patients (Fig. 1, B), MCP joints of 3, and wrists of 3 (Fig. 4, A). Ten of 17 patients (59%) had definite (Grade 2 or 3) periarticular osteopenia (Figs. 1, A; 2, A; and 3, A), and 8 had diffuse osteopenia. Joint-space narrowing was noted in 7 patients (41 %), involving the DIP [ 1], PIP [6], MCP [1], and wrist [1] (Fig. 3, C) joints. Nine patients exhibited definite erosive lesions; these were located in the DIP [4] (Fig. 2, B), PIP [9] (Figs. 1, B; 4, B; 6, B; and 6, C), MCP [5] (Fig. 3, C), wrist or carpal joints [6] (Fig. 3, A and B), and ulnar styloid [3] (Fig. 4, A). Resorption of the distal phalangeal tuft was found in 6 patients (Fig. 5), and 6 had soft-tissue atrophy over the distal phalanx (Fig. 1, A). A sequential study of fine-detail radiographs was available for patient A.E. Over a 21-month interval (January 1973 to September 1974) there was progression from minimal (Grade 1) to definite (Grade 2) erosions in the MCP joints and from minimal to deeper pocketed (Grade 3) erosions in the DIP and PIP joints (Fig. 6, B and C). Three of 5 seropositive (rheumatoid factor) patients had erosive lesions. There were 6 additional patients with erosive disease, representing 36 % of the seronegative group.
MATERIALS AND METHODS
Fourteen women and 3 men with MCTD were studied. They ranged in age from 18 to 63 years (mean 38.6 years) and the duration of symptoms prior to study was 1-24 years (mean 7 years). The clinical and serologic findings in this group were similar to those described for MeTD (TABLE I). All patients had a positive antinuclear antibody test and hemagglutinating antibodies to the ribonuclease-sensitive ENA, termed ribonucleoprotein (10-15).2 Patients with anti-Sm antibodies were excluded from the study as this is thought to be present primarily in systemic lupus erythematosus (SLE) (10). Rheumatoid factor was measured by a standard latex fixation method. Radiographs of the hands of all patients were obtained with a fine-detail, non-screen technique with Kodak Type M film as previously described (1, 4, 6-9). Radiographs were processed and examined at four to eightfold optical magnification (8, 9). These were graded for diffuse and periarticular osteopenia, soft-tissue swelling, joint-space narrowing, and bony erosion according to the following scale (9): 0 (none), 1 (borderline), 2 (definite), and 3 (severe).
1 From the Departments of Radiology of The University of Chicago Hospitals and Clinics (E.J.U., ChiefResident) and the University of California Medical Center at San Francisco (H.K.G., Associate Professor of Radiology), and the Departments of Medicine of the Medical College of Wisconsin (F.K., Assistant Professor of Medicine) andthe University of California at San Diego(M.G., Assistant Professor of Medicine). Revised manuscript accepted for publication in February 1977. 2 These studies were kindly performed by Dr. Gordon C. Sharp, University of Missouri Medical School, Columbia, Missouri, or Dr. EngM. Tan, Scripps Clinic & Research Foundation, La Jolla, California. shan
613
614
ERIC
J.
UDOFF AND OTHERS
September 1977
Fig. 1. A and B. Moderate juxta-articular demineralization associated with periarticular soft-tissue swelling and abnormal tapering of the distal soft tissues (A). Close-up view of proximal interphalangeal joint of this patient (8) demonstrates capsular distension and early surface erosion of the phalangeal condyle (arrows).
DISCUSSION
Connective tissue overlap syndromes in which features of several distinct diseases are present have been studied previously (2, 3, 16). The group described here with mixed connective tissue disease (MCTD) is unique in that it is associated with a specific antinuclear antibody directed at a saline extractable antigen, ribonucleoprotein (10-15). Clinically, the MCTD is characterized by features of scleroderma (Raynaud's phenomenon, skin changes, dysphagia), systemic lupus erythematosus (skin rash, serositis, fevers, lymphadenopathy), polymyositis, and rheumatoid arthritis (15). It appears to be an important subgroup of the "collagen vascular" diseases in that there is a lower incidence of serious renal involvement and a more predictable response to corticosteroid therapy (14, 15). The radiographic characteristics of the MCTD have not been examined systematically as yet, although a recent report of 3 cases demonstrated a variety of joint and soft-tissue changes (16). In our group of 17 patients studied by the technique of fine-detail radiography, the pattern of joint disease was diverse, mimicking the clinical diversity of the syndrome. Features of scleroderma (tuft resorption and DIP erosions), rheumatoid arthritis (erosive arthritis),
and systemic lupus erythematosus (deforming, nonerosive arthritis) were apparent. Radiographs of one patient demonstrated progressive erosive disease. Several patients had entirely normal radiographs. Of interest was the observation that 36 % of seronegative patients exhibited bony erosions. It is possible that this represented scleroderma joint disease in 2 patients (S.8., F.P.), as there was associated distal tuft resorption; it is also possible that patients with the MCTD constitute a subgroup of so-called seronegative rheumatoid arthritis. The results presented here must be interpreted with caution in view of the highly selected nature and relatively small group of patients. However, it is important that the radiologist recognize this newly described, serologically distinct connective tissue syndrome, mixed connective tissue disease, in which the clinical diversity is reflected by the radiographic diversity.
Eric J. Udoff, M.D. Department of Radiology University of Chicago 950 East 59th Street Chicago, III. 60637
Diagnostic Radiology
Fig. 2. A and B. Striking subluxation of interphalangeal joint of the thumb and advanced ulnar deviation with subluxation of the second through fifth metacarpophalangeal joints (A). Moderate juxta-articular demineralization is also demonstrated. Close-up view of distal interphalangeal joint of this patient (B) shows surface erosion and crumbling of subchondral bone.
Fig. 3. A-C. Juxta-articular demineralization and erosive articular disease (A). Close-up view of the wrist (B) shows near-total loss of cartilage in the carpal and radiocarpal joints associated with erosive articular disease. Ulnar drift of the carpus is also demonstrated. Close-up of the MCP joints (C) demonstrates joint narrowing, erosive articular disease and mild reactive sclerosis of the second MCP joint.
615
Fig. 4. A and 8. Close-up view of ulnar styloid demonstrating pocketed erosion and overlying soft-tissue swelling. Proximal interphalangeal joint of this patient (8) shows similar erosive articular disease of the condyles.
Fig. 5. Resorption of a portion of the distal phalangeal tuft is shown.
Fig. 6. A-C. Subtle surface erosions (closed arrows) of the metacarpal head and base of proximal phalanx simulating early rheumatoid arthritis (A). In (8) and (C) progressive erosions (open arrows) of the proximal interphalangeal joint can be seen occurring over a 21-month period.
616
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51-M
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81,920 16,000
320
10,240 2,560 2,560 80 20,480
AntiRNp 2
100,000 ( 10) 10,000 ( 0) 10,000 ( 0) 10,000 ( 0) 100,000 ( 10)
100,000 (10) 100,000 (10)
Pos
6
Pos" Pos"
AntiENA 3
-
+
-
-
-
+
-
-
-
+
+ + +
+ + +
+
+
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+ + +
+
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-
-
+
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-
+
+ +
-
-
+
-
+
+ + +
+
+
-
+ +
-
+
-
+ + + + +
+ + +
-
+
+
+ -
+ + +
Raynaud's Hand Phenom- Swelling enon
-
RF 4
Arthritis
Clinical Findings
+
0
+
-
-
+
0
0
+
-
+
-
-
-
-
+
-
-
-
-
+
-
+
+ +
0 0
-
0 + + +
7/18
+
+
+
+
+ + +
Abnormal Abnormal PulPolyEsoph- monary myositis ageal Func(Muscle Motility tion Biopsy)
15/18 16/18 12/18 8/14 5/16 1+ = Present; - = absent; 0 = not tested. 2Anti-RNP antibodies expressed as reciprocal titer (performed by Dr. Eng M. Tan). 3Anti-ENA antibodies before and after (in parenthesis) ribonuclease digestion (performed by Dr. Gordon Sharp). "Rheumatoid factor as reciprocal titers by sensitized sheep cell or latex fixation tests; positive = titer> 180. STotal WBC count
