Undifferentiated Connective Tissue Disease - In-Depth Overview

For Physicians


Jessica R. Berman, MD

Associate Attending Physician, Hospital for Special Surgery
Associate Professor of Medicine, Weill Cornell Medical College

  1. Definition
  2. Pathogenesis
  3. Clinical Presentation
  4. Laboratory Findings
  5. Differential Diagnosis
  6. Initial Treatment
  7. Long-Term Management Issues
  8. Prognosis
  9. When to Refer
  10. Annotated Bibliography

 

I.  Definition

The term "undifferentiated connective tissue disease" (UCTD) describes those patients who have clinical features and certain laboratory markers that are suggestive of a systemic autoimmune disorder, or connective tissue disease but who lack sufficient characteristics for a well-defined connective tissue disease, such as rheumatoid arthritis, lupus, or scleroderma.

This undifferentiated category is a distinct entity from "overlap syndromes" in which patients have enough features of more than one connective tissue disease to simultaneously meet the criteria for several, and thus "overlap" two or more diseases. (For example, mixed connective tissue disease [MCTD] is just such an "overlap" syndrome.)

In contrast, patients with UCTD will not have enough of the features of any one rheumatic disease to be firmly classified as such by the currently established diagnostic criteria but may have features from several known diseases and are therefore said to be "undifferentiated."

The term undifferentiated connective tissue disease was first used in 1980's to identify a subset of patients who were recognized as being in the early stages of a connective tissue disease (CTD) but who did not yet meet the standard criteria for a well-defined CTD. At that time, it was noted that a substantial proportion of these patients remained undifferentiated or experienced a disease remission and never evolved in to a more defined rheumatic disease. Other names used early on to describe some of these patients included "latent lupus" and "incomplete lupus erythematosus," meaning that some features suggestive of lupus are present, but not enough to fulfill the criteria for the disease. As many as a quarter of all patients seen by rheumatologists can be placed in the "undifferentiated" connective tissue disease category.

Many investigators have been studying these patients in an attempt to identify the most common serologic profiles, factors that may be predictive of evolution in to a well-defined connective tissue disease, and markers for prognosis. It is currently believed that only about 6-20% of patients with UCTD go on to develop features of a definite connective tissue disease. As many as one-third will experience a remission of their symptoms. The rest continue with generally mild disease in the undifferentiated form.

II. Pathogenesis

The cause of UCTD, like many rheumatic diseases, is not well understood. There is speculation that genetic factors or exposure to viruses may play a role in disease initiation or etiology, as has been raised for other CTD, but this has never been studied in UCTD.

Several other more controversial etiologies such as occupational exposures, solvents and implanted medical devices have been looked at in several different studies. However, no clear link can be convincingly demonstrated at this time.

Unfortunately, there have not yet been any rigorous attempts to define the basic science of UCTD. Future attempts at studying UCTD will surely be complicated by the heterogeneity seen in this population of patients.

At the present time, it is presumed that many of the same immunologic mechanisms that play a role in lupus and RA may be at work, but specific ones have not been described. Immune dysregulation at some level must be present to account for the disease manifestations of UCTD. Potential factors involved may include altered antigen presentation and antigen processing, loss of tolerance, altered apoptosis and complement activation. A resultant change in cytokine profile is likely a factor in the disease process, although the particular ones involved are not yet known.

III. Clinical Presentation

In the studies of patients that have been done to date, nearly all authors report that the most common clinical features of UCTD are:

  • arthralgias,
  • arthritis,
  • Raynaud's phenomenon,
  • rash,
  • fever,
  • oral ulcers,
  • photosensitivity,
  • sicca symptoms,
  • alopecia.

Occasionally serositis (pleuritis or pericarditis) and neuropathy occur. Renal disease or serious central nervous system disease is almost never described.

The overwhelming majority of these patients do not develop end-organ damage or life-threatening manifestations. The hallmark of UCTD is its mild course and low likelihood of progression.

There are no commonly accepted criteria yet, as there are for many other rheumatic diseases, although a preliminary one has recently been proposed by Mosca, et al, as follows:

Preliminary Classification Criteria for UCTD
  • Signs and symptoms suggestive of a CTD, but not fulfilling the criteria for any of the defined CTDs, for at least three years
  • Presence of antinuclear antibodies (ANA) identified on two different occasions

It will be important in the future to define carefully this subset of patients so that the term UCTD does not become a "wastebasket diagnosis." Clarification of the definition will make it easier to properly study issues of prognosis, disease etiology, and treatment.

IV. Laboratory Findings

A. Immunologic

While most studies note that the majority of patients with UCTD are ANA positive, the broad range of immunologic abnormalities also seen in these patients includes: positive anti-Ro/SSA, positive anti-SM, positive anti-RNP, elevated ESR, hypergammaglobulinemia, positive rheumatoid factor (RF), positive anti-dsDNA, antiphospholipid antibodies, and hypocomplementemia. A positive serologic test for syphilis has also been described.

A recent study identified anti-Ku antibodies (antibodies to a DNA-binding nuclear protein complex) in a variety of connective tissue diseases. These are frequently found in association with anti-Ro/SSA antibodies. The three UCTD patients in this study all were all found to be positive for the Ku antibody. Further study is needed to determine whether anti-Ku antibodies will ultimately have predictive value in UCTD.

B. Hematologic

Thrombocytopenia, leukopenia, and anemia may also occur in patients with UCTD. These may parallel disease activity and are rarely severe enough to require treatment alone.

C. Predictive Value of Laboratory Findings

Multiple studies have attempted to determine which, if any, laboratory features may predict the evolution of UCTD to SLE or other connective tissue diseases.

In a study of 148 patients who had detectable anti-Ro/SSA antibodies and a diagnosis of UCTD for at least one year, leukopenia was more frequent in those patients who ultimately developed a defined connective tissue disease. Anti-dsDNA antibodies were predictive of evolution to SLE. However, the majority of patients in this study who developed a CTD progressed to primary Sjogren's syndrome (50%).

Another study found that anti-RNP antibodies were significantly correlated with Raynaud's phenomenon and arthritis. Anti-Ro antibodies correlated with xerostomia and xerophthalmia. Most interestingly, 82% of those studied were found to have a simple autoantibody profile characterized by a single specificity. The serologic profile of these UCTD patients remained unchanged in follow-up.

Among those UCTD patients with features more suggestive of lupus (termed incomplete lupus or ILE), it has been noted in a cohort of 87 that elevated dsDNA and decreased C4 were associated with subsequent development of lupus. Others have noted that the presence of homogeneous ANA and presence of anti- Sm antibody were predictive of lupus occurrence.

One physical finding which is thought to be predictive of evolution to a defined CTD is abnormal nail-fold capillaries. One study followed 43 patients with UCTD and found that abnormal capillary length and width showed a significant predictive value for the development of UCTD into systemic sclerosis (SSc); 10 of the patients (23%) progressed to definite SSc. Similar studies have suggested that the rate of progression might be even higher. However, nailfold capillary abnormalities have been seen in many other diseases, such as dermatomyositis, lupus, and Sjogren's syndrome, and psoriasis. Nail-fold capillaries are easily visualized utilizing an opthalmoscope at +40 diopters, or a dissecting microscope with powers ranging from 20x to 40x, with mineral oil applied to the nail bed. These are also called stereo microscopes or wide field microscopes.

V. Differential Diagnosis

Other well-defined connective tissue diseases are clearly in the differential, including rheumatoid arthritis, SLE, myositis, Sjogren's Syndrome, and scleroderma. Diffuse body pain without other objective features, even in the presence of a positive ANA, argues more strongly for fibromyalgia than a true connective tissue disease.

A thorough history, exam and laboratory evaluation to rule out these other rheumatic diseases is important. In this sense, the diagnosis of UCTD is one of exclusion. When the suspicion of an autoimmune disease is high in a patient because several features of one or more of these diseases is present, but signs and symptoms are insufficient to meet their criteria, UCTD is diagnosed. However, the threshold for reconsideration of a more definite CTD must be low if, and when, new symptoms present in such patients.

VI. Initial Treatment

No formal study of various treatments in patients with UCTD has been conducted. Most therapies are borrowed from experiences of their effectiveness in the manifestations of other rheumatic diseases. It is unknown to what degree a particular therapy improves the symptoms of UCTD or decreases the rate of flare or the likelihood of evolution to a more defined connective tissue disease.

Most therapies are symptomatic and include:

  • analgesics and non-steroidal anti-inflammatory drugs for musculoskeletal symptoms;
  • topical corticosteroids and anti-malarials such as hydroxychloroquine (Plaquenil) for mucocutaneous manifestations.

For symptoms refractory to these measures, occasionally low dose steroids are useful for short periods of time. High doses of steroids, cytotoxic agents, and immunosuppressives are almost never used.

However, a study of methotrexate effects in non-renal lupus patients also looked at its effects in 15 UCTD patients whose most common clinical findings were positive ANA, non-erosive polyarthritis, and Raynaud's phenomenon. Overall efficacy was noted in eight patients (53%). Response was best in patients with dermatitis (5/6), arthritis (6/13), and myositis (1/1), but minimal for CNS symptoms (1/4) and serositis (1/3). Nine patients (60%) experienced some toxicity, with five (33%) discontinuing the drug. Although this study was small, it suggests that this may be an effective disease-modifying drug for UCTD, especially for those patients with predominantly arthritis and dermatitis, and should be further studied.

VII. Long-Term Management Issues

Pregnancy: outcome, impact on flare rate and disease evolution

To date there has only been one study addressing the issue of pregnancy in patients with UCTD. Out of 25 pregnancies in 20 patients with the diagnosis for at least one year, 22 pregnancies (88%) were successfully brought to term. Complications were observed in six out of 22 of the successful pregnancies (27%), most commonly low birth weight or preterm delivery.

Flares of disease were noted in six patients (24%) and included arthritis, fever, and skin rash. One patient developed systemic lupus erythematosus. The flare rate was higher than the incidence of flares in a control population of non-pregnant UCTD patients, suggesting that close follow-up of these patients during pregnancy is warranted.

Monitoring for Thyroid Disease

Thyroid disease, especially hypothyroidism, is a common autoimmune condition which can be seen more frequently in patients with other autoimmune diseases such as SLE and RA. One small study of 75 patients with UCTD showed that thyroid disease was present in 6%, and that patients without symptoms of thyroid disease had, on average, higher TSH levels, suggesting that monitoring UCTD patients for the occurrence of thyroid disease may be appropriate.

Work up for Subclinical Pulmonary Disease

One interesting study examined the use of bronchiolar lavage in patients with UCTD and subclinical pulmonary disease as demonstrated by chest X-ray, chest CT scan, or pulmonary function testing. The study showed that in patients with UCTD, a predominantly lymphocytic alveolitis can be found. Whether this has any diagnostic or prognostic usefulness has not been demonstrated, but the findings are intriguing and may ultimately be of use in caring for such patients.

VIII. Prognosis

Patients with UCTD have an excellent prognosis. Almost all studies to date indicate a low likelihood of progression to any organ involvement, such as renal, pulmonary, or central nervous system disease. A small minority of patients (<20%) go on to develop a well-defined connective tissue disease, but this becomes much less likely if the disease has been present unchanged for greater than five years. In a substantial proportion of patients, the disease is mild and no treatment is needed. The majority of patients can be treated symptomatically, and very few patients ever require the use of immunosuppressive medications.

IX. When to Refer

Patients with suspected UCTD should be evaluated initially by a rheumatologist to exclude the presence of another definite connective tissue disease.

Once symptoms have been stabilized with effective medical management, routine monitoring should be done by a rheumatologist at least twice a year. Checking renal and liver function and blood counts several times a year is sufficient unless new symptoms develop. Any new symptoms should be promptly evaluated and the possibility of evolution in to a well-defined connective tissue disease considered.

X. Annotated Bibliography

Alarcon GS. Unclassified or undifferentiated connective tissue disease. Baillieres Best Practice Clin Rheumatol. 2000 Mar; 14(1): 125-37.
A good review of the 10-year clinical outcomes in UCTD.

Alarcon GS, Willkens RF, Ward JR, Cleeg DO, Morgan J, Ma K, Singer J, Steen V, Paulus H, Luggen M, Polisson, Ziminski C, Yarboro C, Williams H. Early undifferentiated connective tissue disease. IV. Musculoskeletal manifestations in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of patients with well-established connective tissue diseases: followup analyses in patients with unexplained polyarthritis at baseline. Arthritis and Rheum 1996; 39: 403-414.
At five years, 47% of patients with unexplained polyarthritis retained that diagnosis.

Calvo-Alen J, Alarcon GS, Burgard SL, Burst N, Bartolucci AA, Williams HJ. Systemic lupus erythematosus: predictors of its occurrence among a cohort of patients with early undifferentiated connective tissue disease: multivariate analyses and identification of risk factors. J Rheumatol 1996 Mar; 23(3): 469-75. This study attempted to identify characteristics in UCTD patients that may predict evolution of UCTD to SLE and may help the physician identify patients at higher risk.

Cavazzana I, Franceschini F, Belfiore N, Quinzanini M, Caporali R, Calzavara-Pinton P, Bettoni L, Brucato A, Cattaneo R, Montecucco C.
Undifferentiated connective tissue disease with antibodies to Ro/SSa: clinical features and follow-up of 148 patients.
Clin Exp Rheumatol 2001 Jul-Aug;19(4):403-9
As many as a quarter of patients with early connective tissue disease and Ro antibodies will develop a defined CTD.

Clegg DO, Williams HJ, Singer JZ, Steen VD, Schlegel S, Ziminski C, Alarcon GS, Luggen ME, Polisson RP, Willkens RF, et al. Early undifferentiated connective tissue disease. II. The frequency of circulating antinuclear antibodies in patients with early rheumatic diseases. J Rheumatol 1991 Sep;18(9):1340-3.
Specific antibodies are relatively insensitive and seen in low frequency in UCTD

Danieli MG, Fraticelli P, Franceschini F, Cattaneo R, Farsi A, Passaleva A, Pietrogrande M, Invernizzi F, Vanoli M, Scorza R, Sabbadini MG, Gerli R, Corvetta A, Farina G, Salsano F, Priori R, Valesini G, Danieli G.
Five-year follow-up of 165 Italian patients with undifferentiated connective tissue diseases. Clin Exp Rheumatol 1999 Sept-Oct; 17(5): 585-591.
Another study showing low rate of evolution of UCTD after five years and limited use of steroids and immunosuppressive drugs.

Danieli MG, Rossetti L, Fraticelli P, Malcangi G, Testa I, Danieli G. Autoimmune thyroid disease in patients with undifferentiated connective tissue disease. Clin. Rheumatol. 2000; 19(1):42-6.
Suggests that autoimmune thyroid disease may be more common in patients with UCTD, as is often the case for patients with other autoimmune diseases.

Franceschini F, Cavazzana I, Generali D, Quinzanini M, Viardi L, Ghirardello A, Doria A, Cattaneo R. Anti-Ku antibodies in connective tissue diseases: clinical and serological evaluation of 14 patients. J Rheumatol 2002 Jul; 29(7): 1393-7.
Anti-Ku antibodies are seen in a variety of autoimmune rheumatic diseases, including the 3 patients with UCTD included in this study.

Kumanovis G, Zibotics H, Juhasz E, Komocsi A, Crirjak L. Subclinical pulmonary involvement assessed by brochiolar lavage in patients with early undifferentiated connective tissue disease. Clin Exp Rheumatol. 2001 Sep-Oct; 19(5): 551-9.
UCTD patients with subclinical lung disease by CXR, CT or PFTs have a predominenetly lymphocytic infiltrate on BAL.

Laing TJ, Schottenfeld D, Lacey JV Jr, Gillespie BW, Garabrant DH, Cooper BC, Heeringa SG, Alcser KH, Mayes MD. Potential risk factors for undifferentiated connective tissue disease among women: implanted medical devices. Am J Epidemiol 2001 Oct 1;154(7):610-7
Case-control study of 205 UCTD patients finds there may be a small but significant association of disease occurrence with prosthetic joints and metallic implants but not silicone devices.

Mosca M, Neri R, Bencivelli W, Tavoni A and Bombardieri S. Undifferentiated connective tissue disease: analysis of 83 patients with a minimum followup of 5 years. J Rheumatol 2002 Nov;29(11): 2345-9.
Rate of evolution of UCTD into another well defined CTD is higher during the first few years after onset.

Mosca M, Neri R, Bombadieri S. Undifferentiated connective tissue diseases (UCTD): A review of the literature and a proposal for preliminary classification criteria Clin Exp Rheumatol 1999 Sept-Oct: 17(5): 615-620. Review
This paper addresses the important issue of the need to systematically categorize those patients who should most appropriately be termed "undifferentiated." Classification criteria are proposed.

Mosca M, Neri R, Strigini F, Carmignani A, Totti D, Tavoni A, and Bombardieri S. Pregnancy outcome in patients with undifferentiated connective tissue disease: a preliminary study on 25 pregnancies. Lupus 2002; 11(5): 304-7.
This important study finds UCTD patients are at higher risk of pregnancy complications despite the assumption that UCTD is generally "mild" and appropriately argues for careful monitoring of these patients during pregnancy.

Mosca M, Tavoni A, Neri R, Bencivelli W and Bombardieri S. Undifferentiated connective tissue diseases: the clinical and serological profiles of 91 patients followed for at least 1 year. Lupus 1998; 7(2): 95-100.
UCTD patients have a stable antibody profile after one year of disease. UCTD seems to represent a distinct clinical entity rather than the early phase of a definite connective tissue disease given that evolution after one year of disease is low.

Ohtsuka T, Tamura T, Yamakage A, Yamazaki S. The predictive value of quantitative nailfold capillary microscopy in patients with undifferentiated connective tissue disease. Br J Dermatol 1998 Oct;139(4):622-9
23% of UCTD patients with abnormal nailfold capillaries went on to develop systemic sclerosis.

Swaak AJ, van de Brink H, Smeenk RJ, Manger K, Kalden JR, Tosi S, Marchesoni A, Domljan Z, Rozman B, Logar D, Pokorny G, Kovacs L, Kovacs A, Vlachoyiannopoulos PG, Moutsopoulos HM, Chwalinska-Sadowska H, Dratwianka B, Kiss E, Cikes N, Anic B, Schneider M, Fischer R, Bombardieri S, Mosca M, Graninger W, Smolen JS; Study group on incomplete SLE and SLE with disease duration longer than 10 years. Incomplete lupus erythematosus: results of a multicentre study under the supervision of the EULAR Standing Committee on International Clinical Studies Including Therapeutic Trials (ESCISIT). Rheumatology (Oxford) 2001 Jan;40(1):89-94
Only a small minority of patients with incomplete SLE will go on to develop SLE.

Vila LM, Mayor AM, Valentin AH, Garcia-Soberal M, Vila S. Clinical outcome and predictors of disease evolution in patients with incomplete lupus erythematosus. Lupus 2000;9(2):110-5.
In patients with "incomplete lupus" malar rash, oral ulcers, elevated dsDNA and low C4 were associated with progression to SLE.

Williams HJ, Alarcon GS, Joks R, Steen VD, Bulpitt K, Clegg DO, Ziminski CM, Luggen ME, StClair EW, Willkens RF, Yarboro C, Morgan JG, Egger MJ, Ward JR. Early undifferentiated connective tissue disease (CTD). VI. An inception cohort after 10 years: disease remissions and changes in diagnoses in well established and undifferentiated CTD. J Rheumatol 1999 Apr 26(4): 816-25.
This includes data on patients with UCTD followed over 10 years (the longest documented study) and makes the important observation that even with disease this far out, many patients still have not evolved into a more defined CTD.

Williams HJ, Alarcon GS, Neuner R, Steen VD, Bulpitt K, Clegg DO, Ziminski CM, Luggen ME, Polisson RP, Willkens RF, Yarboro C, Morgan J, Egger MJ, Ward JR. Early undifferentiated connective tissue disease. V. An inception cohort 5 years later: disease remissions and changes in diagnoses in well established and undifferentiated connective tissue diseases. J Rheumatol 1998 Feb;25(2):261-8.
Patients with the initial diagnosis UCTD followed for five years tended to remain undifferentiated or remitted.

Wise CM, Vuyyuru S, Roberts WN. Methotrexate in nonrenal lupus and undifferentiated connective tissue disease - a review of 36 patients. J Rheumatol 1996 Jun; 23(6): 1005-10.
This small study suggests that methotrexate may be an effective disease-modifying drug for UCTD, especially in those patients with predominantly arthritis and dermatitis.


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