Undifferentiated systemic rheumatic (connective tissue) disease and overlap syndromes

INTRODUCTION — Patients with undifferentiated systemic rheumatic disease (USRD) and/or overlap syndromes present with a constellation of symptoms and laboratory abnormalities that do not clearly fall into one disease subtype. They may manifest multiple nonspecific clinical or serologic abnormalities, sometimes of more than one defined rheumatic disorder (table 1). As much as 25 percent of patients with rheumatic disease and systemic symptoms cannot be definitively diagnosed; the majority of these patients remain undiagnosed during 5 to 10 years of follow-up [1-3].

This topic review provides an overview of USRD and overlap disorders, together with an overall approach to these patients. Mixed connective tissue disease (MCTD), which is sometimes considered under the umbrella of USRD, may have similar clinical features in the presence of high-titer anti-U1 ribonucleoprotein (RNP) antibodies and is discussed in detail separately. (See "Mixed connective tissue disease".)

TERMINOLOGY — The terms undifferentiated systemic rheumatic disease (USRD) and undifferentiated connective tissue disease (UCTD) refer to the same clinical scenario, where patients have features suggestive of a systemic rheumatic disease but the exact type cannot be differentiated [3-11]. Increasingly, the term "systemic rheumatic" disease has replaced "collagen," "collagen-vascular," and "connective tissue" disease. This change reflects the recognition that these disorders probably represent perturbations of the immune system with resultant inflammatory tissue injury rather than primary disorders of collagen, vasculature, or connective tissue. We will use both USRD and UCTD in our discussion as these are both referred to in the literature.

TYPES OF UNDIFFERENTIATED SYSTEMIC RHEUMATIC DISEASE — The disorders generally considered to be undifferentiated systemic rheumatic disease (USRD) and/or overlap syndromes are presented in the table (table 1). USRD and overlap syndromes typically comprise one or more of the following clinical scenarios:

●Nonclassic or early presentations of specific syndromes – This includes patients who present with features suggestive of a specific condition (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis [RA], or systemic sclerosis) but have enough diagnostic uncertainty to preclude a diagnosis.

●Undifferentiated arthritis syndromes – This includes undifferentiated polyarthritis syndrome and undifferentiated spondylarthritis.

●Overlap syndromes – Some patients with rheumatic diseases have systemic features that overlap two or more specific, recognized entities [2,3,12-14]. Overlap syndromes can occur in all possible combinations of rheumatologic/autoimmune symptoms, most commonly including patients with features of SLE, RA, systemic sclerosis, polymyositis/dermatomyositis, juvenile idiopathic arthritis (JIA), and/or Sjögren's disease [15]. Some of these conditions occur with sufficient frequency that they have been given their own unofficial designations (eg, "rhupus" for the overlap of RA and SLE, and "sclerodermatomyositis" for systemic sclerosis and dermatomyositis).

●Mixed connective tissue disease (MCTD) – Patients with MCTD may have symptoms of multiple types of autoimmune conditions (eg, SLE, systemic sclerosis, RA, and polymyositis) in the presence of high-titer anti-U1 ribonucleoprotein (RNP) antibodies. This condition is discussed in detail separately. (See "Mixed connective tissue disease".)

●Undifferentiated connective tissue disease (USRD) – This includes patients with features suggestive of systemic autoimmune disease who do not otherwise fit into the above categories.

DIAGNOSTIC CHALLENGES — There are many challenges in making an early and specific diagnosis of systemic rheumatic disease, including the following:

●Overlapping clinical manifestations – There is overlap in the clinical manifestations of multiple systemic rheumatic diseases, including rheumatoid arthritis (RA), Sjögren's disease, systemic lupus erythematosus (SLE), systemic sclerosis, and inflammatory myopathy. Common symptoms include Raynaud phenomenon (RP), inflammatory arthritis, interstitial lung disease (ILD), pleuritis, and, less often, pericarditis and small vessel vasculitis. In addition, systemic rheumatic diseases may initially present with few nonspecific symptoms, such as malaise and fatigue. (See 'Clinical manifestations' below.)

●Nonspecific serologic abnormalities – Various diseases may share serological abnormalities, such as positivity for antinuclear antibodies (ANAs), rheumatoid factor (RF), anti-Ro/SSA, and anti-La/SSB. Autoantibodies may be present years before the onset of symptoms of systemic autoimmune disease [16]. (See "Measurement and clinical significance of antinuclear antibodies", section on 'Nonrheumatologic causes of a positive ANA'.)

In addition to not being specific to one type of systemic autoimmune disease, some autoantibodies are not specific to systemic rheumatic disease and can be present in low or even moderate/high titer in healthy individuals (eg, ANAs) [17]. Other antibodies have greater diagnostic value [18], including anticyclic citrullinated protein/peptide (CCP) antibodies in RA; anti-Smith, anti-double-stranded deoxyribonucleic acid (dsDNA), and antiphospholipid antibodies in SLE; and anticentromere and anti-topoisomerase-I (Scl-70) antibodies in limited cutaneous systemic sclerosis (CREST syndrome) and diffuse cutaneous systemic sclerosis, respectively. (See "Biologic markers in the assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies' and "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Laboratory testing' and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Laboratory testing'.)

●Limitations of diagnostic criteria – The American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR; formerly known as the European League Against Rheumatism) have issued diagnostic criteria for many specific systemic rheumatic diseases. Most of these diagnostic criteria are not intended for clinical use and were designed to help identify a homogenous patient population for research. Consequently, they often favor specificity over sensitivity and may exclude patients with early or atypical presentations.

●Confusion between overlap syndromes and drug-induced SLE – Patients with one rheumatologic condition can sometimes develop drug-induced lupus, which can mimic an overlap syndrome. As an example, tumor necrosis factor (TNF)-alpha inhibitors are commonly used to treat RA and are associated with drug-induced lupus and the induction of multiple autoantibodies. Thus, discretion is needed in differentiating a true overlap disorder from one that is drug induced. (See "Drug-induced lupus", section on 'Clinical presentation'.)

Given these multiple challenges, it is not surprising that clinicians frequently care for patients who do not neatly fit into one category of systemic rheumatic disease and are hence categorized as having undifferentiated systemic rheumatic disease (USRD) and/or overlap syndromes. It is estimated that 15 to 25 percent of tertiary rheumatology referrals are for patients who do not present with a clearly defined autoimmune/rheumatologic syndrome or who have overlapping features of two or more diseases [1,2].

CLINICAL MANIFESTATIONS

Range of symptoms — Patients with undifferentiated systemic rheumatic disease (USRD) and overlap syndromes may present with a wide range of clinical manifestations. Occasionally, patients may present with nonspecific symptoms such as malaise and fatigue, and diagnostic evaluation will reveal high titers of autoantibodies and other abnormal laboratory tests that suggests possible USRD. More commonly, patients present with one or more symptoms suggestive of a systemic rheumatic disease, such as Raynaud phenomenon (RP), inflammatory polyarthritis, nonspecific rashes, and interstitial lung disease (ILD). Patients may also have other clinical features seen in specific types of systemic rheumatic disease, such as systemic lupus erythematosus (SLE), Sjögren's disease, systemic sclerosis, inflammatory myopathy, and/or vasculitis, but fall short of meeting diagnostic criteria for a single entity.

Common symptoms

Raynaud phenomenon — RP may be an early sign of systemic rheumatic disease in as many as 10 percent of individuals. RP has been associated with many types of systemic autoimmune diseases, including USRD, SLE, systemic sclerosis, and inflammatory myopathies such as antisynthetase syndrome. Studies have found that 8 to 37 percent of pediatric and adult patients presenting with primary RP may eventually be diagnosed with an autoimmune rheumatic disease, including USRD, with rates varying depending on presenting symptoms and duration of follow-up [19,20].

More information about the clinical manifestations and diagnosis of RP, including an evaluation for causes of secondary RP, is detailed elsewhere. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)

Inflammatory arthritis — Some patients with USRD may develop inflammatory arthritis that is suggestive but not diagnostic of rheumatoid arthritis (RA), with positive autoantibodies and a dramatic response to antiinflammatory therapy. Inflammatory arthritis may also be seen in other systemic rheumatic diseases including SLE, systemic sclerosis, and polymyositis/dermatomyositis. Patients with inflammatory arthritis related to USRD may present with some of the following clinical features:

●Symptoms of inflammatory joint disease such as diffuse or migratory arthralgias, prolonged morning stiffness, joint swelling, and/or arthritis. Arthritis may be migratory or persistent, symmetrical or asymmetrical, and oligo- or polyarticular. Symptoms may be persistent or palindromic (ie, recurrent discrete episodes) [21].

●Persistently elevated inflammatory markers (erythrocyte sedimentation rate [ESR] and C reactive protein [CRP]) and a positive antinuclear antibody (ANA), rheumatoid factor (RF), and/or anticyclic citrullinated protein/peptide (CCP) antibodies.

●A dramatic response to antiinflammatory therapy [22,23].

These findings are suggestive of RA but do not fulfill the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) criteria for this diagnosis [24]. It is important to try to accurately diagnose patients and initiate targeted therapy as soon as possible given the risk of irreversible joint damage with many types of inflammatory arthritis, most notably RA.

The general approach to undifferentiated inflammatory arthritis in adults and the evaluation of possible RA are presented elsewhere:

●(See "Undifferentiated inflammatory arthritis in adults".)

●(See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

●(See "Clinical manifestations of rheumatoid arthritis", section on 'Initial clinical presentation'.)

While limited data suggest that magnetic resonance imaging (MRI) may be useful in the evaluation of patients with undifferentiated inflammatory arthritis [25,26], this imaging modality is rarely indicated as part of the initial evaluation. (See "Undifferentiated inflammatory arthritis in adults", section on 'Limited role for imaging to confirm synovitis'.)

When referring to the literature on inflammatory arthritis related to USRD, it is important to note that advances in diagnostic testing over time have decreased the proportion of patients classified with inflammatory arthritis related to USRD. As a key example, anti-CCP antibodies were incorporated into the revised ACR/EULAR criteria for RA in 2010 [24]. This has led to reclassification of some patients who would have otherwise been considered to have undifferentiated arthritis as having RA [27].

Cutaneous lesions — Patients with USRD may have nonspecific rashes, which are often associated with an interface dermatitis (ie, inflammation at the dermal-epidermal junction). Data are limited, but the type and location of skin lesions seem to vary. In one study of 526 individuals with undifferentiated connective tissue disease (UCTD) and antithyroid antibodies, 47 patients had a dermatitis consisting of erythematous macules, patches, or papules with delicate scale; they were most frequently on the lower extremities but were also observed on the upper extremities and back [28]. Skin biopsies in 15 of 47 of these individuals showed mild lymphocytic dermatitis, superficial perivascular infiltrates of mononuclear inflammatory cells that spared eccrine glands, patchy dermal mucin, and occasional lymphocytic vasculopathy. Immunofluorescent staining was not performed.

Interstitial lung disease — Interstitial lung disease (ILD) is associated with USRD as well as many other more specific systemic rheumatic diseases disorders, including SLE, Sjögren's disease, systemic sclerosis, and polymyositis/dermatomyositis. ILD may precede other symptoms of systemic rheumatic disease or occur later once the disease is more established.

A histologic pattern referred to as nonspecific interstitial pneumonia (NSIP) is commonly found in lung biopsy specimens of patients with USRD as well as these other specific systemic rheumatic diseases; an exception is RA, which is more commonly associated with usual interstitial pneumonia (UIP) on pathology [29]. (See "Causes, clinical manifestations, evaluation, and diagnosis of nonspecific interstitial pneumonia" and "Interstitial lung disease in rheumatoid arthritis", section on 'Pathologic patterns'.)

It is important to distinguish when patients have ILD and/or NSIP related to USRD or another systemic rheumatic disease. The response to treatment and prognosis are more favorable for those with NSIP that is associated with rheumatic disease versus those with ILD that is unassociated with rheumatic disease [30,31]. Similarly, survival is better among patients with ILD who have a related systemic rheumatic disease compared with those who do not [29].

The association of NSIP with USRD was illustrated in a case-control study comparing patients with ILD who had one or more features of USRD with patients who had ILD without features of USRD [32]. NSIP was more common among the patients with features of USRD who underwent lung biopsy compared with patients without features of USRD (83 percent of 18 patients and 9 percent of 22 patients, respectively). Other histologic patterns observed in patients with features of USRD included UIP, organizing pneumonia, and nonclassifiable fibrosis (6 percent each).

Several terms have been proposed to categorize patients who have ILD and/or NSIP associated with systemic autoimmune disease:

●The concept of "lung-dominant" connective tissue disease has been proposed to characterize those patients with NSIP who had certain histopathologic features (diffuse perivascular collagen, aggressive pleuritis, lymphoid aggregates with germinal center formation, and/or prominent plasma cell infiltrates) or positive serologies (antisynthetase, Scl-70, SSA, or CCP antibodies) but who lacked sufficient extrapulmonary clinical features to be classified as having a specific rheumatic disease.

●The term "interstitial pneumonia with autoimmune features" (IPAF) was proposed by the European Respiratory Society/American Thoracic Society to describe patients with ILD and features of autoimmunity, which is notably a separate category from patients with ILD in the setting of USRD [33]. However, it has been challenging to identify clinically meaningful differences between patients with IPAF versus those with ILD in the setting of USRD or undifferentiated ILD [34]. The value of efforts to dissect unclassifiable illnesses without a clear understanding of etiologies, pathogenesis, outcomes, and/or therapeutic responses is uncertain.

The general approach to clinical evaluation, diagnostic testing, and possible lung biopsy in ILD is presented separately:

●(See "Approach to the adult with interstitial lung disease: Clinical evaluation".)

●(See "Approach to the adult with interstitial lung disease: Diagnostic testing".)

●(See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

Patients with overlap syndromes — Patients with overlap syndromes may have different clinical presentations than those with single disorders with respect to the timing of the onset of symptoms. In a retrospective analysis of patients with overlap syndromes, patients with rhupus tended to develop clinical manifestations sequentially, whereas those with sclerodermatomyositis tended to have a simultaneous presentation [35,36]. In addition, certain clinical manifestations may be more similar to one of the associated diseases than the other. As an example, arthritis in patients with rhupus may be erosive [14] and associated with anti-CCP antibodies; this presentation is more consistent with RA than with the nonerosive, Jaccoud arthropathy typically seen in SLE [37].

DIAGNOSIS

When to suspect USRD — The diagnosis of undifferentiated systemic rheumatic disease (USRD) and/or overlap syndromes should be suspected in patients who present with a constellation of clinical and laboratory features seen in specific types of systemic rheumatic disease (such as systemic lupus erythematosus [SLE], Sjögren's disease, systemic sclerosis, inflammatory myopathy, and/or vasculitis) but fall short of meeting diagnostic criteria for a single entity.

Diagnostic evaluation — In patients with suspected USRD or overlap syndrome, the diagnostic evaluation primarily focuses on the exclusion of alternative diagnoses, including more specific systemic rheumatic diseases as well as other nonrheumatologic disorders such as infections and cancer. There is no formulaic approach that will fit all patients, nor are there consensus guidelines or other evidence-based approaches [38]. Our approach, which is based upon our clinical expertise, is guided by the patient’s presenting clinical features. (See 'Clinical manifestations' above.)

●We perform a thorough history and physical examination, including fundoscopy and nailfold capillaroscopy. The review of systems should be broad given the many potential manifestations of systemic rheumatic diseases.

●We obtain basic laboratory testing including a complete blood count and differential, complete metabolic panel, and urinalysis with microscopic examination.

●Additional laboratory testing and other studies should be guided based upon the presenting features of the patient but may include the following:

•Inflammatory markers, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

•Autoantibodies, including antinuclear antibodies (ANAs); anti-double-stranded DNA (dsDNA), -Smith, -RNP, -centromere, -Ro/SSA, -La/SSB, -Jo-1, -Scl-70, and -PM1 antibodies; antiphospholipid antibodies; antineutrophil cytoplasmic antibodies (ANCAs); rheumatoid factor (RF); anticyclic citrullinated peptide (CCP) antibodies; and a myositis-specific antibody panel

•Thyroid testing, including thyroid function tests and thyroid peroxidase antibody (TPO)

•Creatine kinase

•Serum protein electrophoresis

•Cryoglobulins

•Testing for infectious diseases (eg, viral hepatitis panel, parvovirus B19)

•Screening for cancer as part of an evaluation for a paraneoplastic syndrome

•Imaging and lung biopsy for patients with interstitial lung disease (ILD)

•Skin biopsy for patients with rash

•Salivary gland ultrasonography, MRI, or labial salivary gland biopsy for patients with concern for possible Sjögren's disease [39]

While testing for myositis-specific antibodies has not yet become standardized, testing in certain clinical scenarios can be useful. Patients with inflammatory myopathies may have amyopathic or hypomyopathic presentations as well as more predominant lung, joint, or skin manifestations. More information about sending myositis-specific antibodies is provided elsewhere. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Myositis-specific autoantibodies'.)

The diagnostic approach to early and/or incomplete presentations of SLE, including definite, probable, possible, and ANA-negative subtypes, is also provided separately. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Our diagnostic criteria'.)

Making a diagnosis — In circumstances of diagnostic uncertainty, we refer to patients with clinical and/or laboratory features suggestive of systemic autoimmune disease as having "USRD" or overlap syndromes [3]. Diagnosis should not be based only on isolated clinical features or certain laboratory or serologic abnormalities. We urge caution in assigning one or more diagnoses (eg, RA and SLE) for patients with symptoms who do not meet currently accepted criteria [3,40-45]. Assigning diagnostic labels to patients implies confidence in the disease pathogenesis, prognosis, treatment, and outcomes. Premature diagnostic closure can lead to inappropriate management and potential harm as well as possible legal consequences.

MANAGEMENT — We manage patients with undifferentiated systemic rheumatic disease (USRD) according to their major rheumatologic symptom(s) and follow patients regularly to monitor for evolving signs and symptoms of more specific diseases.

Approach to treatment — In patients with USRD and/or overlap syndromes, treatment is generally directed towards the patient’s particular clinical manifestations (eg, inflammatory arthritis or interstitial lung disease [ILD]) and is not predicated on a definitive diagnosis. Patients who have minimal or nonspecific symptoms (eg, fatigue or malaise) can be managed conservatively with supportive therapies. Patients with more specific symptoms can be treated with therapies guided by the severity of the symptom. We may also favor certain treatments based on the similarity of the patient’s clinical presentation to more specific types of rheumatic diseases (eg, rheumatoid arthritis [RA] or systemic lupus erythematosus [SLE]). As an example, patients who have mild arthralgias without definitive evidence of synovitis might benefit from a trial of nonsteroidal antiinflammatory drugs (NSAIDs), while those who have arthritis and antibodies suggestive of possible SLE may benefit from a trial of hydroxychloroquine (HCQ).

More detail on the management of Raynaud phenomenon (RP) and ILD is provided separately. (See "Treatment of Raynaud phenomenon: Initial management" and "Overview of the management of adults with interstitial lung disease".)

Data to support specific types of treatment for patients with USRD and overlap syndromes is extremely limited:

●Hydroxychloroquine – It is our practice to consider a trial of HCQ for patients with USRD or overlap syndromes who have at least three months of inflammatory polyarthritis. In such cases, we use shared decision-making with the patient and set a timeline and expectations for symptom improvement. This approach is based on the authors' expertise, given the lack of randomized controlled trials and very limited observational data. We generally do not give HCQ to patients who are asymptomatic with positive autoantibodies or who only have nonspecific symptoms such as fatigue or brain fog.

When HCQ is used to treat inflammatory arthritis in USRD, the dosing, monitoring, and potential adverse effects are the same as when it is used for other types of rheumatic diseases, which are described in more detail elsewhere. (See "Antimalarial drugs in the treatment of rheumatic disease".)

Data to support the use of HCQ in patients with USRD are very limited. In a retrospective study of 130 American military personnel who eventually developed SLE, patients who were taking HCQ prior to the diagnosis of SLE had a longer time from symptom onset to diagnosis compared with those who were not taking HCQ (median 1.08 versus 0.29 years), suggesting that HCQ may have delayed the onset of further clinical manifestations [46]. In addition, patients who received HCQ acquired autoantibodies at a lower rate. Data supporting the use of HCQ in treating inflammatory arthritis in related conditions, including SLE and RA, is detailed elsewhere. (See "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Hydroxychloroquine' and "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Mild to moderate symptoms'.)

●Methotrexate – In a series including 15 patients with undifferentiated connective tissue disease (UCTD), methotrexate (MTX) was most effective for the treatment of arthritis and dermatitis but had little effect on central nervous system abnormalities or on serositis [47].

More information about the use of MTX in patients with rheumatic diseases is provided elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Treatment of arthritis'.)

●Vitamin D – It may be reasonable to screen patients for vitamin D deficiency, which is the practice of some of the authors; however, data supporting this approach are limited. In a small study of 21 patients with UCTD and vitamin D deficiency, vitamin D supplementation was associated with improvement in immunoregulatory function (Treg/T17 ratio) after five weeks [48]. This suggests that correction of vitamin D deficiency might decrease the likelihood of developing progressive manifestations of systemic autoimmune disease.

Limited data suggest that vitamin D supplementation may reduce the incidence of a variety of autoimmune diseases, although patients with USRD were not specifically studied. In a double blind trial, the incidence of new autoimmune conditions was lower in adults (males ≥50 years old and females ≥55 years old) who were randomly assigned to receive vitamin D versus those who received placebo for a five-year period (hazard ratio [HR] 0.78, 95% CI 0.61-0.99) [49]. A follow-up study noted that the benefit was not sustained over the subsequent two years [50].

More information about the treatment of vitamin D deficiency is provided elsewhere. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

Follow-up — Follow-up intervals will reflect the nature and severity of symptoms, rapidity of change in clinical manifestations (if any), and patient and clinician comfort with the diagnostic uncertainty. In general, we see and evaluate patients with new-onset RP or new onset of inflammatory arthritis monthly for the first three months. We follow patients with other specific clinical manifestations as often as we would see patients with recognized rheumatic diseases that can include such manifestations. Finally, we generally see relatively asymptomatic patients at intervals of approximately six months.

At follow-up evaluations, we consider repeating diagnostic studies based on the patient’s clinical picture, including the presence of any new clinical manifestations. This approach is individualized for the care of each unique patient with USRD. In general, we do not advocate for repeating autoantibody testing unless doing so would allow a patient to be diagnosed with SLE. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Diagnosis'.)

We avoid diagnostic labels not clearly supported by established criteria and only offer a specific diagnosis beyond USRD (eg, SLE, RA) if patients evolve to fulfill the appropriate classification criteria. We tolerate uncertainty as best we can and help patients and caregivers accept this as well.

Considerations around pregnancy — Some patients with USRD and/or overlap syndromes may have potential pregnancy-related complications related to specific clinical features or laboratory tests. As examples, patients with anti-Ro/SSA antibodies are at risk of the fetus developing neonatal heart block, and symptoms related to ILD and pulmonary hypertension can worsen due to physiologic changes during pregnancy. Thus, if a patient is considering pregnancy or is pregnant, we often repeat testing for anti-Ro/SSA antibodies and antiphospholipid antibodies and consider screening for ILD and pulmonary arterial hypertension.

We provide additional counseling for patients who are known to have features suggestive of specific systemic rheumatic diseases (eg, overlap syndromes) and/or positive anti-Ro/SSA antibodies, which are detailed separately:

●(See "Rheumatoid arthritis and pregnancy".)

●(See "Pregnancy in women with systemic lupus erythematosus".)

●(See "Systemic sclerosis (scleroderma) and pregnancy".)

●(See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis", section on 'Screening and surveillance'.)

There are limited observational data on pregnancy in patients with USRD to support these recommendations. Studies generally suggest that the risk of certain complications is higher for patients with USRD compared with healthy individuals, but lower when compared with patients who have SLE:

●In a longitudinal cohort study, 150 patients with "early," "incomplete," or "preclinical" autoimmune systemic rheumatic disease had an increased risk of having small-for-gestational-age infants and preeclampsia or fetal growth restriction when compared with healthy patients (9.3 versus 18.7 percent, and 5.1 versus 14.7 percent respectively) [51].

●A series of 100 pregnancies in patients with UCTD reported 11 first-trimester miscarriages, 89 live births, and 13 flares during pregnancy or puerperium, three of which were major and led to development of SLE with kidney disease [52]. There were 26 obstetrical complications among the 89 successful pregnancies (29 percent), including one case of preeclampsia. A significant link between anti-dsDNA at baseline and disease activity at the beginning of pregnancy was noted. The impact of pregnancy on disease in these patients was thought to be less than for patients with other rheumatic diseases.

●In another study of pregnancies that compared 51 patients with UCTD with 150 women with SLE, the frequencies of prematurity and preeclampsia were significantly lower than those with high-activity SLE. Pregnancy outcomes in patients with UCTD and low-activity SLE were similar to those in healthy women [53].

DISEASE COURSE AND PROGNOSIS — There are limited observational data to guide the prognosis of undifferentiated systemic rheumatic disease (USRD) in general, as well as for patients who present with specific clinical manifestations.

Patients with USRD — Evolution from USRD to a discrete rheumatic disease is somewhat more common than resolution of USRD. In general, a definitive rheumatic disease is diagnosed in 10 to 35 percent of patients 3 to 10 years from disease onset [11,54-60]; the most common eventual diagnoses include systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), systemic sclerosis, Sjögren's disease, rheumatoid arthritis (RA), vasculitis, and, less commonly, polymyositis/dermatomyositis [54,55,57]. Evolution occurs within two to five years after the initial presentation in the majority of cases [59]. In a multicenter study that evaluated a cohort of 213 patients with symptoms of early USRD for at least one year who were then followed for five years, the rate of progression to RA or SLE was 20 and 13 percent, respectively. Complete remission is unusual, occurring in 6 to 24 percent [11,54,55,57,61]. It should be noted that patients with early or incomplete manifestations of specific autoimmune diseases, such as SLE and RA, can still accrue tissue damage [62,63].

Although not well characterized, the presence of certain clinical features may predict evolution into specific diseases [11,57,64-66]. In a meta-analysis of patients with undifferentiated connective tissue disease (UCTD), serositis and kidney disease were the two clinical features that were most strongly predictive of progression to SLE [67]; a positive Coomb's test, thrombocytopenia, hypocomplementemia, and presence of certain autoantibodies (dsDNA, Smith, anti-Ro/SSA, anticardiolipin) were also associated with progression. Among patients who were ultimately diagnosed with systemic sclerosis, features associated with progression included puffy fingers, abnormal nailfold capillaries, and antitopoisomerase-I antibodies. In other retrospective studies, cytopenias, an ANA titer >1:640, anti-Ro/SSA positivity, anticentromere positivity, and abnormal nailfold capillaroscopy have also been associated with evolution to specific diagnostic entities [61,66].

There is ongoing research into biomarkers that may predict the likelihood of developing specific autoimmune diseases. As an example, levels of B-lymphocyte stimulator (BLyS or BAFF; a cytokine involved in SLE pathogenesis) [68] and expression of type I and type II interferon (IFN)-gene products [69] differ in patients who have SLE compared with those who have suggestive clinical features without a definitive diagnosis.

Patients with specific clinical manifestations

Raynaud phenomenon — Nailfold capillaroscopy can provide important prognostic insights for patients with RP. A study followed 308 patients who presented with Raynaud phenomenon (RP) without other clinical laboratory features to suggest connective tissue disease, but who had pathologic features on nailfold capillaroscopy that were concerning for evolving connective tissue disease [70]. Of the 133 patients who had follow-up data after a mean of 6.5 years (range: 1 to 15 years), 109 had been diagnosed with connective tissue disease; compared with patients who did not develop connective tissue disease, these patients were more likely to have had certain features on nailfold capillaroscopy including giant capillaries, avascular fields, and irregular architecture of nailfold capillaries.

Other clinical and laboratory features that have been associated with underlying systemic rheumatic disease in patients presenting with RP include older age of onset, severe digital ischemia, asymmetrical RP attacks, thumb involvement, and the presence of antinuclear antibodies (ANAs) [71,72]. The presence of ANAs alone, however, should not lead to a premature diagnosis of underlying systemic rheumatic disease. In a prospective study of patients presenting with RP, a defined rheumatic disease developed in only 22 percent of the 129 patients who had a positive ANA without a systemic rheumatic disease at initial presentation [73]. In addition, the presence of anticentromere antibodies among patients presenting with RP is associated with the eventual development of limited cutaneous systemic sclerosis (CREST syndrome); in one series of 85 patients presenting with primary RP or with possible connective tissue disease, the presence of anticentromere antibodies had a sensitivity of 60 percent and specificity of 98 percent for the development of CREST [74].

Inflammatory arthritis — Patients who initially present with inflammatory arthritis and are unable to be clearly diagnosed with RA often evolve over time. In a study of 435 patients with "early" RA who were seronegative, there was significant reclassification and diagnostic heterogeneity during the 10-year follow-up period [75]; the most common reclassifications were to polymyalgia rheumatica (16 percent), psoriatic arthritis (11 percent), osteoarthritis (10 percent), and spondyloarthritis (9 percent). In two large prospective studies done prior to the widespread use of anticyclic citrullinated protein/peptide (CCP) antibodies, approximately 20 percent of patients with inflammatory arthritis attributed to USRD evolved into definite RA [11,76]. A consistent pattern of predictive variables could not be identified in the multivariate analyses other than higher small joint counts and higher erythrocyte sedimentation rate (ESR) after one year [11] as well as rheumatoid factor (RF) positivity [76].

For patients with undifferentiated inflammatory arthritis, it is not clear whether early intervention with a disease-modifying antirheumatic drug (DMARD) may alter the natural progression from undifferentiated arthritis to RA or other specific rheumatic diseases [77]. Clinical trials of preventive therapies for RA are discussed in detail elsewhere. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis", section on 'Prevention of RA'.)

There are conflicting data from observational studies on whether the prognosis differs for patients who have undifferentiated arthritis and those with RA. In a one-year observational study, 42 percent of the 77 patients with undifferentiated arthritis had progressive disease; their outcomes (radiographic progression and health assessment questionnaire [HAQ] score at one year) were not significantly different than those for the 203 patients with RA [78]. By contrast, in a longer observational cohort study of 1141 patients (638 with undifferentiated arthritis and 503 with RA), symptoms completely resolved after seven years in 54 percent of those with undifferentiated arthritis versus only 7.5 percent of those with RA at presentation [76]. Anti-CCP antibodies were notably not used in either study, meaning some patients with CCP-positive, RF-negative RA might have been misclassified as having undifferentiated arthritis.

Autoantibodies and other laboratory values that may be early identifiers or risk factors for RA are discussed in detail elsewhere. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis", section on 'Physiologic risk factors or identifiers of preclinical RA' and "Biologic markers in the assessment of rheumatoid arthritis".)

Interstitial lung disease — Studies have not clearly identified any features that are associated with progression of interstitial lung disease (ILD) to USRD or other classifiable systemic rheumatic diseases. In a series of 68 patients who had presented with ILD and who were followed prospectively for 11 years, 13 (19 percent) eventually developed classifiable rheumatic disease; there were no significant differences in clinical or histologic features between patients who developed systemic rheumatic disease versus those who did not [79].

SUMMARY AND RECOMMENDATIONS

●Types of undifferentiated systemic rheumatic disease – Undifferentiated systemic rheumatic disease (USRD) and/or overlap syndromes (table 1) include (see 'Types of undifferentiated systemic rheumatic disease' above and "Mixed connective tissue disease"):

•Nonclassic or early presentations of specific syndromes (ie, features suggestive of a specific rheumatic disease who have enough diagnostic uncertainty to preclude a diagnosis)

•Undifferentiated arthritis syndromes (eg, undifferentiated spondyloarthritis)

•Overlap syndromes (ie, features that overlap two or more specific, recognized entities)

•Mixed connective tissue disease (MCTD; ie, symptoms of multiple types of autoimmune conditions in the presence of high-titer anti-U1 ribonucleoprotein [RNP] antibodies)

•USRD (features suggestive of systemic autoimmune disease who do not otherwise fit into the above categories)

●Diagnostic challenges – Specific autoimmune diseases are challenging to diagnose due to overlapping clinical features, limited specificity of some autoantibodies, and diagnostic criteria that often exclude patients with early or atypical presentations. (See 'Diagnostic challenges' above.)

●Clinical manifestations – Occasionally, patients may present with nonspecific symptoms such as malaise and fatigue, and diagnostic evaluation will reveal abnormal laboratory testing that suggests possible USRD. More commonly, patients present with one or more symptoms suggestive of a systemic rheumatic disease, such as Raynaud phenomenon (RP), inflammatory polyarthritis, nonspecific rashes, and interstitial lung disease (ILD). Patients may also have other clinical features seen in specific types of systemic rheumatic disease (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis [RA]). (See 'Range of symptoms' above.)

●Diagnosis

•When to suspect USRD – The diagnosis of USRD and/or overlap syndromes should be suspected in patients who present with a constellation of clinical and laboratory features seen in specific types of systemic rheumatic disease (such as SLE, Sjögren's disease, systemic sclerosis, inflammatory myopathy, and/or vasculitis) but fall short of meeting diagnostic criteria for a single entity. (See 'When to suspect USRD' above.)

•Diagnostic evaluation – In patients with suspected USRD or overlap syndrome, the diagnostic evaluation primarily focuses on the exclusion of alternative diagnoses, including more specific systemic rheumatic diseases as well as other nonrheumatologic disorders such as infections and cancer. We perform a thorough history and physical examination, including fundoscopy and nailfold capillaroscopy. We obtain basic laboratory testing, including a complete blood count and differential, complete metabolic panel, and urinalysis with microscopic examination. Additional laboratory testing and other studies should be guided based upon the presenting features. (See 'Diagnostic evaluation' above.)

•Making a diagnosis – In circumstances of diagnostic uncertainty, we refer to patients with clinical and/or laboratory features suggestive of systemic autoimmune disease as having "USRD" or overlap syndromes. Diagnosis should not be based only on isolated clinical features or certain laboratory or serologic abnormalities. We urge caution in assigning one or more diagnoses (eg, RA and SLE) for patients with symptoms who do not meet currently accepted criteria. (See 'Making a diagnosis' above.)

●Management

•Approach to treatment – In patients with USRD and/or overlap syndromes, treatment is generally directed towards the patient's particular clinical manifestations (eg, inflammatory arthritis or ILD) and is not predicated on a definitive diagnosis. Patients who have minimal or nonspecific symptoms can be managed conservatively with supportive therapies. Patients with more specific symptoms can be treated with therapies guided by the severity of the symptom. We may also favor certain treatments based on the similarity of the patient’s clinical presentation to more specific types of rheumatic diseases (eg, RA or SLE).

In patients with USRD or overlap syndromes who have inflammatory polyarthritis for at least three months, we suggest a trial of hydroxychloroquine (HCQ) rather than an alternative disease-modifying antirheumatic drug (DMARD) (Grade 2C). (See 'Approach to treatment' above.)

More detail on the management of RP and ILD is provided separately. (See "Treatment of Raynaud phenomenon: Initial management" and "Overview of the management of adults with interstitial lung disease".)

•Follow-up – Definitive rheumatic diseases are ultimately diagnosed in 10 to 35 percent of patients, typically within two to five years of the initial presentation, underscoring the importance of close follow-up. Follow-up intervals will reflect the nature and severity of symptoms, rapidity of change in clinical manifestations (if any), and patient and clinician comfort with the diagnostic uncertainty. (See 'Follow-up' above and 'Disease course and prognosis' above.)