Connective tissue disease clinical diagnosis

by Nathan Wei, MD, FACP, FACR

Nathan Wei is a nationally known board-certified rheumatologist and author of the Second Opinion Arthritis Treatment Kit. It's available exclusively at this website... not available in stores.

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The term "undifferentiated connective tissue disease" (UCTD) describes patients who have clinical features and laboratory markers that suggest a systemic autoimmune disorder, but who lack the signs and symptoms of a well-defined connective tissue disease, such as rheumatoid arthritis, lupus, or scleroderma.

The following is from a review presented by the American College of Rheumatology and its members... ( I apologize for misplacing the exact reference upon which this review is based)

This undifferentiated category is different from "overlap syndromes" where patients have features of more than one connective tissue disease.

Patients with UCTD will not have enough features of any one rheumatic disease to be classified by diagnostic criteria (American College of Rheumatology). They may have features from several diseases and are therefore called "undifferentiated."

As many as a quarter of all patients seen by rheumatologists can be placed in the "undifferentiated" connective tissue disease category.

Many investigators have studied these patients in order to identify the most common blood profiles, factors that may be predictive of evolution to a more well-defined connective tissue disease, and markers for prognosis. It is 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.

The cause of UCTD, like many rheumatic diseases, is not understood.

Future attempts at studying UCTD will be complicated by the lack of uniform presentation 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. Immune dysregulation at some level is present.

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

• Arthralgias (joint aches)
• Arthritis( joint inflammation)
• Raynaud's phenomenon(fingers blanching and turning white)
• Rash
• Fever
• Oral ulcers(mouth sores)
• Photosensitivity( rashes with sunlight exposure)
• Sicca symptoms(dry eyes and dry mouth)
• Alopecia(hair loss)

Occasionally serositis (pleuritis or pericarditis- inflammation of the ling of the lungs and heart) and neuropathy (nerve damage) occur. Kidney disease or serious central nervous system disease almost never occurs.

The overwhelming majority of these patients do not develop end-organ damage or life-threatening problems. 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.

While most studies note that the majority of patients with UCTD are ANA positive, many other laboratory blood abnormalities can be seen including: 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.

Low blood cell counts for red cells, white cells, and platelets may also occur in patients with UCTD. These may parallel disease activity and are rarely severe enough to require treatment alone.

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, low white blood cell counts 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 dry eyes and dry mouth. 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 group of 87 patients, 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 (blood vessels at the base of the fingernails). 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.

Other well-defined connective tissue diseases are in the list of possible causes of a patient’s symptoms. These include rheumatoid arthritis, SLE, myositis, Sjogren's Syndrome, and scleroderma. Diffuse body aches and pains 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, immediate reconsideration of diagnosis is indicated when new symptoms present in such patients.

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 rarely 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. 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.

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.

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.

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.

Selected references: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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