Autoimmunity Reviews 6 (2006) 1 – 4
www.elsevier.com/locate/autrev
Undifferentiated connective tissue diseases (UCTD)
M. Mosca ⁎, C. Tani, C. Neri, C. Baldini, S. Bombardieri
Rheumatology Unit, Department of Internal Medicine, University of Pisa, Via Roma, 67, 56126 Pisa, Italy
Available online 19 April 2006
Abstract
The term undifferentiated connective tissue diseases is used to define conditions characterized by the presence of signs and
symptoms suggestive of a systemic autoimmune disease that do not satisfy the classificative criteria for defined connective
tissue diseases (CTD) such as systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), rheumatoid arthritis (RA) and
others.
A small percentage of patients presenting with an undifferentiated profile will develop during the first year follow up of a
full blown CTD, however an average of 75% will maintain an undifferentiated clinical course. These patients may be defined as
having a stable undifferentiated connective tissue diseases (UCTD).
The most characteristic symptoms of UCTD are represented by arthritis and arthralgias, Raynaud's phenomenon,
leukopenia, while neurological and kidney involvement are virtually absent. Eighty percent of these patients have a single
autoantibody specificity, more frequently anti-Ro and anti-RNP antibodies.
Stable UCTD are considered as distinct clinical entities and therefore it has been proposed to define those conditions as
UCTD. Classificative criteria have also been proposed and a work to better define them is still under way.
© 2006 Published by Elsevier B.V.
Contents
1. Undifferentiated connective tissue diseases.
2. Clinical and serological manifestations . . .
3. Classificative criteria . . . . . . . . . . . .
4. Conclusions . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . .
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1. Undifferentiated connective tissue diseases
The clinical onset of connective tissue diseases may
be undifferentiated and its common clinical experience
is the existence of conditions characterized by the presence of clinical and serological manifestations suggestive of autoimmune diseases but not sufficient to make a
diagnosis of a defined CTD [1–9], these conditions have
⁎ Corresponding author.
1568-9972/$ - see front matter © 2006 Published by Elsevier B.V.
doi:10.1016/j.autrev.2006.03.004
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1
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3
been variably defined as incomplete systemic lupus
erythematosus, latent lupus, early undifferentiated connective tissue diseases, undifferentiated connective tissue diseases [10–30].
The main clinical manifestations at onset of these
undefined diseases are represented by arthralgias (66%),
arthritis (32%), Raynaud's phenomenon (38%), leukopenia (24%), xerostomia and xerophthalmia (21%), thrombocytopenia (9%), serositis (4%), photosensitive rash
(3%). It may be difficult to distinguish these conditions
2
M. Mosca et al. / Autoimmunity Reviews 6 (2006) 1–4
from early phases of defined diseases such as systemic
lupus erythematosus (SLE), Sjögren's syndrome (SS),
rheumatoid arthritis (RA), systemic sclerosis (SSc) and
many others. It is well known, in fact, that the onset of
many defined CTDs may not be characterized by disease
specific manifestations, such as for example glomerulonephritis in SLE.
Therefore, in the assessment of patients presenting
with an undifferentiated onset, it would be important to
be able to understand whether this is the onset of a
defined disease or rather a condition that will remain
undefined over time [10]. From the existing literature it
is evident that an average of 25% of patients with an
undifferentiated disease at onset will evolve to defined
CTDs during the follow up; the evolution occurring
early in the disease and generally within the first 5 years
of follow up [11,12,15,17–25,27–30].
As reported in Table 1, undifferentiated diseases may
evolve to various defined CTDs, although the evolution to
SLE seems to occur more frequently [11,12,15,17–25,27–
30]. Predictive factors for the evolution to defined CTDs
have been identified (Table 2) [15,17,19,21–25,27–30]. In
particular the presence of anti-dsDNA antibodies, of antiSm antibodies, anti-phospholipid antibodies or the presence of multiple antibodies specificities and among clinical manifestations, serositis, alopecia, photosensitivity
and discoid rash, were predictive for an evolution to SLE
in many studies [15,19,21,27–30].
Less data are available concerning predictive factors
for the evolution to other CTDs. Raynaud's phenomenon,
xerostomia, anti-Ro and anti-La antibodies were correlated with an evolution to SS [28,30]. Raynaud's phenomenon, sclerodactyly, esophageal dysfunction, positive
ANA with nucleolar pattern were correlated with an evolution to SSc [21,30]. Polyarthritis, positive rheumatoid
factors, and an increased ESR were correlated with a
possible evolution to RA [30].
It is important to note, however, that these latter
associations, derive from single studies and probably
Table 1
Evolution of undifferentiated diseases to defined connective tissue
diseases (CTD)
Defined CTD
Author
SLE
SLE+other CTD:
• LES
• SS
• SSp
• MCTD
• PM
• AR
[11,12,17,27]
[15,19,21–23,28,30]
8–21%
2–18%
4–15%
0.5–3%
0.6–2%
3–26%
Table 2
Predictive factors for the evolution to defined connective tissue
diseases (CTD)
No predictive variables
[11,17]
Predictive variables identified
• Clinical variables
• Serological variables
[15,21,30]
[15,19-21,28-30]
reflect the different assessment that patients undergo at
the time of diagnosis and therefore need to be interpreted cautiously.
No triggering factors for the evolution of undifferentiated diseases to defined CTDs have been so far identified, therefore it appears important to strictly monitor
patients particularly at disease onset and also in particular conditions, such as for example pregnancy, which
are known to interfere with the clinical course of systemic autoimmune diseases [29].
2. Clinical and serological manifestations
From the data reported it appears that a small percentage of patients with an undifferentiated onset, will
evolve to defined CTDs while the majority of them will
remain undifferentiated during the course of the disease.
Many authors have used the term undifferentiated connective tissue diseases (UCTD), to identify stable undifferentiated diseases. In the next part of this paper we
will therefore use the definition UCTD to refer to stable
undifferentiated conditions.
There are no specific signs or symptoms of UCTD, in
fact as previously reported, these diseases present clinical
manifestations common to other CTDs. The most frequent
clinical manifestations of UCTD are arthralgias (37–80%),
arthritis (14–70%), Raynaud's phenomenon (45–60%),
leukopenia (11–42%), anemia, xerostomia (7–40%),
xerophthalmia (8–36%). Other clinical manifestations
are reported in Fig. 1 [11–14,16,17,21,24,25,27–31].
It is clear that the clinical profile of UCTD is
characterized by the absence of major organ involvement, particularly kidney and central nervous system and
is generally mild. During the follow up the symptoms
improve and mild disease flares are seen occasionally.
About 90% of the UCTD patients have positive
ANA; anti-Ro antibodies are present in 8–30% of the
patients and anti-RNP in 10–30%. Less frequently positive anti-dsDNA anti-phospholipid antibodies are observed [14,17,19,21,22,26–29]. Interestingly, 80% of
these patients have a simple autoantibody profile characterized by a single antibody specificity, usually antiRo or anti-RNP antibodies [17,28,29].
M. Mosca et al. / Autoimmunity Reviews 6 (2006) 1–4
3
100
90
80
70
60
50
40
30
20
10
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Fig. 1. Clinical manifestations of stable undifferentiated connective tissue diseases (UCTD).
The autoantibody profile remains stable over time
and new autoantibody specificities are rare and usually
observed in those patients who will evolve to defined
CTDs [17].
As these are mild and benign conditions, only a small
percentage of UCTD are treated. The most widely used
drugs are NSAID (40%), low dose corticosteroids (30–
50%) and antimalarials (10–30%) [12,17,27].
3. Classificative criteria
Classificative criteria generally accepted and validated,
able to identify UCTD patients are not yet available. On the
basis of the existing literature, however, preliminary classificative criteria have been proposed to distinguish between early and stable undifferentiated diseases.
On the basis of these criteria UCTD are those conditions characterized by (i) signs and symptoms suggestive
of a connective tissue disease, but not fulfilling the criteria
for any defined CTDs, (ii) positive antinuclear antibodies,
and (ii) a disease duration of at least 3 years. Patients with a
shorter follow up should be defined having as early UCTD
and include patients who will develop a defined CTD and
those with transitory manifestations [23].
4. Conclusions
Undifferentiated connective tissue diseases are systemic autoimmune conditions characterized by a mild
clinical profile and a simplified autoimmune repertoire.
Although these conditions are generally benign, an evo-
lution to CTDs is reported and changes in the disease
course may occur. Therefore a regular follow up of these
patients is advised particularly in the first year of the
disease. A strict monitoring is also advised in conditions
which may interfere with the course of autoimmune
diseases such as for example pregnancy.
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Anti-Jo-1 antibody positive polymyositis – successful therapy with leflunomide
Idiopathic inflammatory myopathies (IM), including dermatomyositis (DM) and polymyosistis (PM), are a group of
systemic rheumatologic diseases of unknown etiology characterized by chronic myositis. Antisynthetase antibodies
such as the anti-Jo-1 antibody are known to be highly specific for inflammatory myopathies. Patients with this antibody
frequently show a combination of symptoms including interstitial lung disease, fever, polyarthritis, myositis, Raynaud's
phenomenon and "mechanic's hands". In the management of PM with anti-Jo-1 antibody, immunosuppressive agents
are used to control the disease. Leflunomide is a new immunosuppressive drug recently introduced in the treatment of
female patients with PM and anti-Jo-1 antibodies. In this study, Lange U. et. al. (Autoimmunity 2006; 39: 261-4) report
two cases of female patients with PM and anti-Jo-1 antibodies, who were successfully treated with leflunomide.