INTRODUCTION — In some patients with inflammatory arthritis, it is not possible to establish a specific diagnosis during the first several weeks to months following symptom onset, although such patients, with undifferentiated early inflammatory arthritis, require effective treatment for their condition to begin to alleviate the symptoms and functional impairment associated with active disease, ie, active inflammation of any one or more joints in terms of synovitis as manifested by joint swelling [1-6].
Inflammatory arthritis is characterized by an influx of inflammatory cells, such as monocytes/macrophages, lymphocytes, and granulocytes, from the blood stream into the synovial membrane or their accrual in the synovial fluid, and is frequently associated with hyperplasia of synovial fibroblasts. This inflammatory process causes pain, swelling (and in some instances redness) of the joint, frequently associated with reduced mobility and functional impairment; moreover, in some diseases damage to cartilage and bone can ensue, leading to joint destruction. Inflammatory arthritis contrasts from osteoarthritis, which is regarded a degenerative joint disease, or mere arthralgia, which may have many causes. In many non-English-speaking countries, the term "inflammatory arthritis" is regarded as pleonastic, since the term "arthritis" as an "-itis" already indicates inflammation, and other diseases, such as osteoarthritis, are named "arthrosis." However, for the sake of this review and for clarity, we will retain the term.
The term "undifferentiated arthritis" (UA) is used here to describe patients with early inflammatory arthritis, typically between six weeks and a year in duration, whose disease cannot yet be clearly diagnosed or clearly differentiated from other defined disorders, although a diagnosis can often be determined within three months and only infrequently requires as long as a year to become evident. Many such patients will eventually be diagnosed with rheumatoid arthritis (RA) after further evolution of the symptoms and findings. In others it may fully subside.
Inflammation is generally reversible, while joint destruction is not, and early and appropriate treatment before a definitive diagnosis can be established may prevent disease persistence, joint damage, and the disability and disease comorbidities associated with the ongoing disease process [1-9]. Early treatment, even without a definitive diagnosis, may also be of benefit because the immunopathologic events mediating the disease process, as in RA, may evolve and differ in later stages from the changes in early disease [10]. Cartilage and bone injury, including erosions, may occur early in the disease course, be irreversible once present, and be associated in RA with greater disease severity, possibly by several mechanisms [11,12]. Whether there is an early "window of opportunity" for inducing remission in RA and other inflammatory arthritides remains uncertain [13]. As an example, a trial of intensive therapies in patients with UA or very early RA rarely resulted in significant efficacy in preventing or reversing disease [14]; and evidence frequently suggested that the evolution of full-blown RA is just delayed but not prevented by early interventions with disease-modifying antirheumatic drugs (DMARDs), including biologic agents [15-17].
The evaluation and management of patients with UA will be presented here. The evaluation of patients with monoarticular and polyarticular pain; synovial fluid analysis; the diagnosis of septic arthritis and gout; and the diagnosis and differential diagnosis of RA, axial and peripheral spondyloarthritis (SpA) (including psoriatic arthritis [PsA]), and other specific forms of arthritis are described in detail separately:
●(See "Monoarthritis in adults: Etiology and evaluation" and "Evaluation of the adult with polyarticular pain".)
●(See "Synovial fluid analysis".)
●(See "Septic arthritis in adults" and "Clinical manifestations and diagnosis of gout".)
●(See "Diagnosis and differential diagnosis of rheumatoid arthritis".)
●(See "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults" and "Clinical manifestations and diagnosis of psoriatic arthritis".)
EPIDEMIOLOGY AND NATURAL HISTORY — An undifferentiated inflammatory arthritis is present in approximately a quarter to a third of patients who have undergone an initial evaluation by an expert in rheumatology in clinics devoted to the evaluation of patients with early arthritis and the facilitation of rapid referral to the appropriate expert in rheumatology [17-19].
The annual incidence of inflammatory arthritis in studies of early arthritis cohorts ranges from 115 to 271 per 100,000 adults [18]. Specific diagnoses could be made at presentation in approximately 70 percent of such patients, the most common being rheumatoid arthritis (RA), but the incidence of undifferentiated arthritis (UA) ranged from 41 to 149 per 100,000 adults, typically approximately 30 percent of the cohort. The most common diagnosis eventually made in patients with UA is RA, although this is in only approximately one-third of the patients; the remaining patients have osteoarthritis, other defined forms of arthritis, or remain undifferentiated, while some undergo spontaneous remission. (See 'Prognosis' below.)
WHEN TO REFER — Patients with inflammatory arthritis in whom a specific diagnosis cannot be readily established should be referred for consultation with an expert in the evaluation and care of patients with rheumatologic disease, such as a rheumatologist, as soon as possible, to assist in making a diagnosis and developing a treatment plan (see "Monoarthritis in adults: Etiology and evaluation" and "Evaluation of the adult with polyarticular pain"). Patients whose diagnosis cannot then be established upon evaluation by an expert in rheumatologic disease can be viewed as having an undifferentiated inflammatory arthritis.
The frequency of subsequent specialist care depends upon the severity of symptoms and joint inflammation, the patient's response to treatment, the complexity and risks associated with the therapy, the preferences of the patient and primary care clinician, and the availability of a rheumatologist. Patients with acute or chronic forms of arthritis have been found to receive better care when assessed and treated by rheumatologists than generalists, both in terms of an earlier specific diagnosis and better outcomes [20-24]. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Care by a rheumatologist'.)
Delays in referral are well-documented, and several strategies have been tried or proposed to help avoid such delays and to facilitate rapid referral [25,26]. These include the use of defined criteria for referral [25,27]; the availability of ready access to the specialists by use of early arthritis clinics, which can reduce the waiting time from contacting the rheumatologist until patients are seen [28,29]; and immediate-access clinics, where patients are seen by an experienced rheumatologist immediately upon (self-)referral for a brief initial assessment, followed by recommendation and referral for a more detailed rheumatology evaluation, if appropriate [29]. During the coronavirus disease 2019 (COVID-19) pandemic, however, access to care was further delayed, and telemedicine approaches were applied with some success [30,31].
DEFINITION AND CLINICAL FEATURES — Patients with undifferentiated inflammatory arthritis do not represent a single disorder in the same sense that a diagnosis of a rheumatologic disease such as gout or rheumatoid arthritis (RA) identifies a disease; rather, undifferentiated arthritis (UA) is a diagnosis of exclusion made in patients with arthritis (a sign and/or symptom of disease), which has caused at least one clinically swollen joint in the absence of further abnormalities sufficient to meet criteria for a specified alternative diagnosis. (See 'Differential diagnosis' below.)
Two factors might be regarded as predictive of RA development in patients with early inflammatory arthritis: (1) the presence of autoantibodies, especially when at least two autoantibodies from among the following are present: rheumatoid factor (RF), anti-citrullinated, anti-carbamylated, and anti-acetylated peptide antibodies [32,33]; and (2) the presence of tenosynovitis [34,35].
An inflamed swollen joint is characterized by soft, rather than hard, tissue swelling along the joint margins due to a joint effusion and/or synovial thickening, usually with some fluctuation upon physical examination. Inflamed swollen joints may be warm and tender, and are sometimes erythematous. The requirement for the presence of at least one clinically swollen joint is similar to the entry requirement for the use of the 2010 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) classification criteria for RA. (See "Evaluation of the adult with polyarticular pain", section on 'Joint examination' and "Diagnosis and differential diagnosis of rheumatoid arthritis".)
A complaint of arthralgia (joint pain) in the absence of at least one inflamed swollen joint on examination, or findings such as pain on motion or tenderness upon pressure, are not sufficient to make a diagnosis of any type of inflammatory arthritis (differentiated or undifferentiated), irrespective of results of sensitive imaging techniques. Indeed, healthy, normal joints may also have power Doppler signals as well as abnormalities on magnetic resonance imaging (MRI) [36-39]. The management strategies outlined for patients with UA (see 'Treatment' below) would not apply to patients with only pain or tenderness, but without a swollen joint.
The clinical features of UA were described in a cohort of 776 patients prospectively evaluated in an early arthritis clinic in the Netherlands [40]:
●Symptoms of arthritis typically ranged from several weeks to months. The median duration of symptoms at presentation was 13.4 weeks (interquartile range [IQR], representing the 25th to 75th percentile, of 5.3 to 29.2 weeks).
●Morning stiffness lasted less than 30 minutes in 46 percent of the patients, 30 to 59 minutes in 16 percent of patients, and at least an hour in 39 percent (median of 30 minutes, IQR 0 to 60 minutes).
●Joint examination showed a swollen joint count of less than 4, 4 to 10, and greater than 10, respectively, in 65, 29, and 6 percent of the patients.
●Arthritis affected the upper extremities in 76 percent of patients, mostly in the hands, with symmetrical involvement in 48 percent.
●Laboratory testing revealed normal levels of acute phase reactants, such as C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) in more than half of the patients, although some patients did have elevated levels (median ESR 16, IQR 8 to 36 mm/h; median CRP 8, IQR 3 to 23 mg/L).
●Positive testing for RF and/or anti-citrullinated peptide antibodies (ACPA) were each present in 10 percent of patients.
DIAGNOSTIC EVALUATION — The medical history, physical examination, and laboratory and imaging studies that should be obtained to determine whether a patient has undifferentiated inflammatory arthritis are directed towards the confirmation of arthritis (rather than a non-arthritic condition) and the exclusion of other disorders through the recognition of features that may lead to the diagnosis of another well-defined disease. Most of these conditions can be readily distinguished from undifferentiated arthritis (UA) by one or more of the following (see 'Differential diagnosis' below and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Differential diagnosis'):
●A history and/or findings on examination of extraarticular features that suggest another diagnosis (eg, a family history of psoriasis)
●Laboratory testing (eg, the presence of autoantibodies)
●Arthrocentesis that facilitates the recognition of an infectious or crystal arthritis
●Imaging studies with abnormal findings that are characteristic of particular arthritic disorders (eg, typical erosions on radiographs characteristic of RA)
The following features are of particular importance:
●History – A thorough medical history should be obtained, with particular attention to current symptoms of arthritis, a past diagnosis of arthritis, and features associated with particular rheumatologic disorders or groups of disorders. These features include (see 'Differential diagnosis' below):
•Symptoms of an infectious illness, urinary tract infection or a recent history or symptoms of urethritis, as in reactive arthritis
•A recent viral syndrome, hepatitis, a tick bite or erythema migrans, which may suggest an infectious etiology
•Symptoms of a spondyloarthritis (SpA), such as inflammatory back pain, heel pain, tendinopathy, or other symptoms of enthesis
•Psoriasis, which may suggest psoriatic arthritis (PsA)
•Symptoms of inflammatory bowel disease, including abdominal pain, diarrhea, blood, or mucus in the stool
•Uveitis or other eye disease, which may be associated with a variety of conditions, including SpA, sarcoid, Behçet syndrome, and other disorders
•Symptoms of systemic rheumatic disease (eg, systemic lupus erythematosus [SLE], systemic sclerosis, or mixed connective tissue disease), including fever, Raynaud phenomenon, alopecia, cutaneous eruptions, mucosal ulcers, pleurisy, pericarditis, and neurologic symptoms
•Symptoms of malignancy, including anorexia, unexplained weight loss, lymphadenopathy, or other changes
The family history should identify, in particular, any history of arthritis, particularly inflammatory arthritis; ankylosing spondylitis; systemic rheumatic disease (eg, SLE); psoriasis; or inflammatory bowel disease.
●Physical examination – A thorough physical examination should be performed to determine if there are signs of extraarticular disease, which may point to an alternative diagnosis, including signs of cutaneous disease, such as psoriasis or a cutaneous eruption suggesting a systemic rheumatic disease (eg, SLE). The patient should undergo a detailed musculoskeletal exam to confirm the presence of inflammatory arthritis, characterize the involved joints, and to identify signs of enthesitis or axial disease.
●Laboratory testing – Laboratory testing should include:
•A complete blood count; blood urea nitrogen and creatinine; hepatic aminotransferases; uric acid; and thyroid-stimulating hormone.
•Autoantibody testing in patients in whom RA or a systemic rheumatic disease has not already been excluded, including rheumatoid factor (RF), anti-citrullinated peptide antibody (ACPA), and antinuclear antibody (ANA).
Additional autoantibody testing in patients with a positive ANA, if a systemic rheumatic disease has not been excluded clinically and there are other signs or symptoms of such a condition. Depending upon the clinical findings, testing may include assays for anti-double-stranded deoxyribonucleic acid (dsDNA), anti-Smith and anti-ribonucleoprotein, anti-Ro/SSA and anti-La/SSB, anti-Jo1, and anti-topoisomerase-1 antibodies. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults".)
Other antibodies and assays, such as anti-carbamylated and anti-acetylated protein antibodies and measurement of 14-3-3eta, respectively, are subjects of research interest, but their clinical utility in this setting has not been established and they are not yet routinely available or widely used [33,41].
•Acute phase reactants, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).
•Human leukocyte antigen (HLA)-B27 testing in patients with signs or symptoms of SpA. (See "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Laboratory testing' and "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults", section on 'Laboratory findings'.)
•Serologic testing for Lyme borreliosis in patients with a recent history of having resided in or traveled to an area endemic for Lyme disease and a risk factor for exposure to ticks; and for parvovirus B19 infection. (See "Diagnosis of Lyme disease", section on 'Serologic tests' and "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Diagnosis'.)
We do not routinely screen for other viral infections; in contrast to parvovirus B19 arthritis, joint disease associated with other viral infections is usually transient ("prodromal symptoms") or associated with additional abnormalities such as fever, lymphadenopathy (eg, Epstein-Barr viral infection), or elevations of liver enzymes (eg, hepatitis B and C).
We prefer to obtain both RF and ACPA because of the utility of both antibodies in helping to make the diagnosis of RA [42-44], although some agencies (eg, the UK National Institute for Health and Care Excellence) suggest first testing for RF and if that is negative also for ACPA [45]. The sensitivity of RF and ACPA for RA is quite similar; ACPA has greater specificity for RA than RF, but can occur in approximately 5 to 15 percent of patients with PsA, Sjögren's syndrome, and occasionally in other diseases [46-53]. While RF can be seen in patients with systemic rheumatic diseases and chronic infections, including hepatitis, it is associated in RA with a higher level of disease activity compared with being positive for ACPA alone [54,55]. Additionally, there is only approximately an 80 percent overlap of the two autoantibody types, although both autoantibodies are associated with destructive disease and precede the occurrence of RA [45-47,56-62]. The detection of autoantibodies to proteins that are modified differently than by citrullination in subsets of patients with seronegative and seropositive RA has reduced the gap between these conditions [63], although assays to detect these additional autoantibodies may not be widely available. (See "Diagnosis and differential diagnosis of rheumatoid arthritis" and "Rheumatoid factor: Biology and utility of measurement", section on 'Clinical disorders associated with rheumatoid factor positivity' and "Biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.)
●Arthrocentesis – Arthrocentesis should be performed in affected swollen joints to exclude diagnoses such as infectious arthritis or crystal disease, if it has not already been performed. Testing should include a cell count, differential, Gram stain, culture, and crystal search. (See "Monoarthritis in adults: Etiology and evaluation", section on 'Joint aspiration'.)
●Imaging – Imaging studies should include:
•In all patients – Plain radiography of the affected joint(s) or region (whole hand or foot even if only one finger/toe is affected) including the contralateral joint region for comparison.
•In patients with symptoms or findings of arthritis affecting the hands – Plain radiographs of both hands and both feet, regardless of whether symptoms or signs of arthritis in the feet are present.
•In patients suspected of RA – Ultrasonography (US) of swollen or tender joints to confirm the presence of synovitis when there is uncertainty regarding joint involvement, if evidence of such involvement will be important in establishing a diagnosis of RA or another disorder, rather than UA, especially when seeking evidence of subclinical synovitis.
Plain radiography is particularly useful because of its utility in identifying findings that are characteristic of RA, particularly joint erosions, which may be useful diagnostically [42,64]. Erosions are found in almost 10 percent of patients with very early RA; they are uncommon in patients in early arthritis clinics, where over 90 percent of patients do not have erosions [65]. Patients with early RA may exhibit erosive changes in the feet even in the absence of local signs and symptoms of involvement. Studies of radiographic changes in patients with UA have also shown that the presence of two or more erosions conveys a high risk of being diagnosed as RA in the near future [66]. Erosive disease has since been defined by European Alliance of Associations for Rheumatology (EULAR; for use in the 2010 American College of Rheumatology [ACR]/EULAR RA classification criteria) as erosions, which are defined as cortical breaks, in at least three separate joints [64]. (See "Clinical manifestations of rheumatoid arthritis", section on 'Plain film radiography' and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Evaluation for suspected RA' and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Patients not meeting above criteria'.)
Both US and MRI may be helpful in identifying involved joints in patients suspected of RA in whom at least one joint is clinically swollen due to synovitis [67-69]. We prefer to use US for this purpose in patients with possible UA given its practicality, low (relative) cost, and accessibility in the outpatient setting compared with MRI. Tenosynovitis (especially at the extensor carpi ulnaris tendon) may be particularly prominent in early RA [70]; it may be easily detected by US. In patients without at least one readily identified clinically involved joint, such studies are less useful, as changes on US may also be present in other diseases and in healthy persons [71]. The prognostic implications in RA of MRI changes, including synovitis and erosions, are uncertain [67,72-76], since their meaning regarding long-term outcomes has not yet been established despite many years of research; however, bone marrow edema in the absence of erosions appears to indicate the presence of microscopic erosions [77]; thus, the presence of bone marrow edema implies that the destructive process in bone has extended into the bone marrow. Moreover, while bone marrow edema may be present in joints of healthy individuals [78], it continues to be most specific for destructive arthritis [79].
On the other hand, erosions detected by MRI can be observed in patients with early arthritis to a similar extent to findings in patients with SLE and Sjögren's syndrome, two diseases in which erosive joint disease is not generally seen by plain radiography, raising further questions regarding the specificity of such MRI findings [36,80]. Sensitive imaging techniques may be helpful in a research setting in defining "pre-clinical arthritis" and allowing the study of therapies to prevent the development of clinically overt arthritis, but there is a lack of evidence to support the use of such techniques for this purpose in routine clinical practice. Moreover, MRI has revealed abnormalities compatible with mild arthritis in more than 70 percent of persons from the general population [37,81]. For all these reasons, the ACR/EULAR RA classification criteria require the presence of at least one clinically swollen joint, but additional joint involvement that may lend further support to classification as having RA can come from imaging findings using ultrasonography or MRI. Overall, the approach described here is consistent with and partly exceeds multinational recommendations for the evaluation of patients with undifferentiated arthritis [82].
DIFFERENTIAL DIAGNOSIS — The principal diagnosis that should be considered in patients who appear to have undifferentiated inflammatory arthritis is rheumatoid arthritis (RA). Other disorders that may appear to represent undifferentiated arthritis (UA) include viral arthritis, which is self-limited, and undifferentiated spondyloarthritis (SpA), as well as the remaining wide range of conditions in the differential diagnosis of monoarthritis and polyarthritis (table 1). These disorders can generally be identified upon evaluation with a thorough history, physical examination, and selected testing. (See "Monoarthritis in adults: Etiology and evaluation" and "Evaluation of the adult with polyarticular pain".)
●Rheumatoid arthritis – RA in its early stages may present as an apparent UA, but characteristically involves a greater number of joints, although the typical symmetric pattern of involvement may not be as evident in early disease when fewer joints may be affected. Patients with RA often have positive testing for rheumatoid factor (RF) and/or anti-citrullinated peptide antibodies (ACPA). Evidence of joint damage is usually lacking in patients with early RA as are extraarticular manifestations, although if such changes are present they may help to establish the diagnosis. (See "Clinical manifestations of rheumatoid arthritis" and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Diagnosis'.)
●Other causes of arthritis – Other than RA, the differential diagnosis of UA (table 1) is highly similar to RA and is discussed in detail separately. Major considerations in the differential diagnosis of an UA include (see "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Differential diagnosis'):
•Viral arthritis (see "Viral arthritis: Approach to evaluation and management", section on 'Diagnosis')
•Peripheral SpA (see "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults")
•Psoriatic arthritis (PsA) (see "Clinical manifestations and diagnosis of psoriatic arthritis", section on 'Diagnosis')
•Reactive arthritis (see "Reactive arthritis", section on 'Diagnosis')
•Arthritis associated with inflammatory bowel disease (see "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases", section on 'Diagnosis')
•Osteoarthritis (see "Clinical manifestations and diagnosis of osteoarthritis", section on 'Diagnosis')
•Lyme arthritis (see "Musculoskeletal manifestations of Lyme disease", section on 'Diagnosis of Lyme arthritis')
•Sarcoidosis-related arthritis (eg, Löfgren syndrome) (see "Sarcoid arthropathy", section on 'Diagnosis')
•Polymyositis/dermatomyositis (see "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Clinical manifestations')
•Systemic sclerosis (scleroderma) with arthritis (see "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Differential diagnosis')
•Systemic lupus erythematosus (see "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults")
Other very uncommon or rare causes of UA include rheumatic fever (see "Acute rheumatic fever: Clinical manifestations and diagnosis", section on 'Diagnosis'), septic arthritis (see "Septic arthritis in adults", section on 'Diagnosis'), hemochromatosis (see "Arthritis and bone disease associated with hereditary hemochromatosis"), paraneoplastic arthritis (see "Malignancy and rheumatic disorders"), mixed connective tissue disease (see "Clinical manifestations and diagnosis of mixed connective tissue disease"), and adult-onset Still's disease. (See "Clinical manifestations and diagnosis of adult-onset Still's disease".)
TREATMENT
Treatment approach — The treatment of patients with undifferentiated early inflammatory arthritis, in whom a specific diagnosis cannot be established after evaluation by an expert in rheumatologic disease (see 'When to refer' above and 'Definition and clinical features' above and 'Diagnostic evaluation' above), is based largely upon the well-established treatments used for rheumatoid arthritis (RA) and spondyloarthritis (SpA). The goal of early therapy, before being able to make a definitive diagnosis, is the suppression of inflammation and the prevention of persistent or recurrent inflammation and joint damage; this goal is most likely to be fulfilled by timely treatment of a patient with undifferentiated arthritis (UA) with a regimen that can achieve disease remission, as it cannot be determined at presentation which patients with UA will develop persistent and/or destructive disease [83]. Given that conventional synthetic disease-modifying antiinflammatory drugs (csDMARDs), such as methotrexate (MTX) and sulfasalazine (SSZ) (and to some extent, leflunomide [LEF]), are effective in RA, psoriatic arthritis (PsA), and peripheral joint involvement in SpA, the exact diagnosis at this undifferentiated state is less important than the timely start of a treatment that interferes with the disease process.
We choose the drug regimen for an individual patient with UA based upon:
●The distribution of the joint involvement and serologic testing, resulting in two clinical categories:
•Disease that generally resembles RA, with prominent upper extremity involvement and/or positive testing for rheumatoid factor (RF) and/or anti-citrullinated peptide antibodies (ACPA)
•Disease that resembles peripheral SpA, with primarily lower extremity involvement and seronegativity for RF and ACPA
●The response to prior or initial therapies
●The severity of disease
In patients with UA, as in RA, we use a multidisciplinary management approach that includes patient education, physical and occupational therapy, and pharmacologic therapy, with shared decision-making by the patient and clinician. The nonpharmacologic interventions are the same as those used for the treatment of RA, including advice regarding smoking cessation. Surgical measures are rarely needed in early stages of arthritis. (See "General principles and overview of management of rheumatoid arthritis in adults" and "Nonpharmacologic therapies for patients with rheumatoid arthritis".)
There have been relatively few trials comparing treatment regimens in patients with UA; our approach is supported by clinical trials and studies in patients with early arthritis, including patients with UA (see 'Rationale for DMARDs in UA' below); the likelihood that the disease will evolve into a more clear-cut diagnosis (most often RA); the similarity of joint involvement in UA to RA or SpA; the efficacy of these approaches in RA, SpA, and related disorders; and clinical experience. (See 'Rationale for DMARDs in UA' below and 'Epidemiology and natural history' above and 'Definition and clinical features' above and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Pharmacologic therapy' and "Treatment of psoriatic arthritis" and "Treatment of peripheral spondyloarthritis".)
Once patients have evolved from UA to a specific diagnosis, which usually occurs within a year or less of presentation, the treatment regimens that should be followed are those that are recommended for the patient's specified disorder (eg, RA or undifferentiated peripheral SpA).
Initial pharmacotherapy — Initial drug therapy of patients with UA, which should follow baseline testing and pretreatment screening, includes both csDMARDs [84], such as MTX or SSZ, combined with antiinflammatory therapies, including systemic and intraarticular glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs), which are primarily adjuncts for temporary control of disease activity. (See 'Pretreatment evaluation' below and 'Initial DMARD therapy' below and 'Adjunctive role of antiinflammatory agents' below.)
Pretreatment evaluation — Studies that should be done prior to starting or resuming therapy with a csDMARD, or intensifying treatment with use of a biologic DMARD (bDMARD), depend upon the medications planned; these studies include baseline routine laboratory testing (complete blood counts, renal and liver chemistries, and acute phase reactants), screening for latent tuberculosis, screening for hepatitis B and C, and immunizations, using the approach taken in patients with RA, which is discussed in detail separately. A baseline chest radiograph should be obtained prior to starting MTX therapy (and will also help exclude sarcoidosis). (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Pretreatment evaluation'.)
Initial DMARD therapy — In patients with UA, we suggest treatment with a csDMARD combined with short-term (<6 months), low-dose (<10 mg) glucocorticoids, rather than only NSAIDs and glucocorticoids without csDMARDs. We do not use a bDMARD for initial therapy of UA. The choice of initial DMARD, usually MTX or SSZ, will depend upon the presumed eventual diagnosis or pattern of clinical involvement, and is based upon the view that patients with prominent upper-extremity involvement or seropositivity for RF or ACPA are more likely to evolve into RA, while patients with prominent lower-extremity involvement are more likely to develop a peripheral SpA [85]. (See 'Upper extremity disease or RF/ACPA-positive' below and 'Seronegative lower extremity predominance' below.)
Therapeutic target — The initial therapeutic goal is to achieve significant clinical improvement within three months, which may be defined as at least a moderate (50 percent) reduction in disease activity using a composite measure such as the Simplified Disease Activity Index (SDAI) or the Clinical Disease Activity Index (CDAI). (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Simplified Disease Activity Index (SDAI)' and "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Disease Activity Score using 28 joints (DAS28)'.)
The goal of continued therapy is to attain remission or low disease activity within the subsequent three months, with remission defined according to the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) definition of remission for patients with RA [86,87]. Of note, ACR and EULAR have updated the Boolean remission definition. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Criteria for remission'.)
This approach for UA is based upon the body of evidence supporting this strategy in patients with RA, consistent with EULAR RA management recommendations; expert opinion and indirect evidence supporting a similar treat-to-target approach for SpA and PsA; preliminary evidence supporting this approach in PsA; and clinical experience in patients with UA [1-3,88-95]. (See 'Rationale for DMARDs in UA' below and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Tight control'.)
Upper extremity disease or RF/ACPA-positive — In patients with UA with upper-extremity involvement or who have a positive test for RF or ACPA, we suggest treatment with MTX rather than other DMARDs. The dose should be gradually titrated up to 20 to 25 mg once weekly to achieve a clinical response (see 'Therapeutic target' above), using the same approach as in patients with RA. As in RA, MTX therapy should be accompanied by folate supplementation to avoid or at least reduce unwanted effects. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate'.)
The use of MTX in such patients is based upon the resemblance of UA with these characteristics (ie, upper-extremity involvement or positive testing for RF or ACPA) to RA, the likelihood that UA in such patients will evolve into RA, and the well-established benefits of MTX in RA, where it is the anchor DMARD for most patients, including those in whom bDMARDs are also required [96-99]. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate' and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Resistant to methotrexate'.)
Alternative therapies include:
●Hydroxychloroquine (HCQ), which may be used in patients with very mild disease activity who are RF- and ACPA-negative, but who clinically resemble RA more than a SpA. HCQ may also have potential benefit as an adjunctive therapy, especially if MTX has induced some improvement but not resolution of UA. (See "Antimalarial drugs in the treatment of rheumatic disease" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Hydroxychloroquine'.)
●SSZ is another alternative for patients unable or unwilling to take MTX; it is also effective in RA, including patients who are RF- or ACPA-positive, and appears safe for use during pregnancy. (See 'Seronegative lower extremity predominance' below.)
●LEF is an alternative for patients with UA in whom the future development of RA or PsA is suspected based upon the medical history and clinical and laboratory findings. As an example, in patients with RA with an inadequate response to MTX, some, but not all, experts switch from MTX to LEF or add LEF to ongoing MTX therapy, depending upon whether there is evidence of some benefit from the MTX and the degree of concern for the possible increased risk of side effects with the combination of LEF and MTX. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Leflunomide'.)
While it is highly unlikely that a patient does not tolerate any of these drugs, alternatives for patients unable to take MTX, SSZ, or LEF include biologic agents, such as an interleukin 6 (IL-6) inhibitor, or a Janus kinase (JAK) inhibitor; IL-6 and JAK inhibitors are superior to tumor necrosis factor (TNF) inhibition as monotherapy.
Seronegative lower extremity predominance — In patients with UA who lack RF or ACPA and have involvement primarily of the lower extremities, we suggest initiating DMARD therapy with SSZ rather than other DMARDs. The dose should be gradually increased up to a maximum of 3000 mg daily, divided into two or three doses, to achieve the desired clinical response (see 'Therapeutic target' above), using the same approach as is used in patients with RA or peripheral SpA. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Sulfasalazine' and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)
The use of SSZ in such patients is based upon the clinical resemblance of UA with these characteristics to peripheral SpA [85], the likelihood that UA in such patients will evolve into a peripheral SpA or RA (see 'Epidemiology and natural history' above), and the demonstrated benefit of SSZ in both peripheral SpA (eg, peripheral arthritis accompanying ankylosing spondylitis or undifferentiated peripheral SpA) and RA. SSZ is a relatively potent DMARD in patients with RA, as indicated by its significant efficacy in reducing the progression of joint damage even when doses are limited to 2000 mg daily. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults", section on 'Sulfasalazine' and "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults" and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults".)
Alternatives for patients unable to take SSZ are MTX or LEF (see 'Upper extremity disease or RF/ACPA-positive' above). Other medications that may be beneficial in these patients when SSZ or one of these alternatives is ineffective include biologic agents, such as a TNF inhibitor or an inhibitor of IL-12/23 or IL-17; we prefer the latter if PsA is suspected.
Pregnancy — In patients who are pregnant or anticipating pregnancy during treatment, regardless of the pattern of joint involvement or testing for RF or ACPA, we prefer to use SSZ, given its relative safety during pregnancy [100-106]. HCQ has also been found safe during pregnancy and can be combined with SSZ in patients with disease resembling RA or used as a single agent in such patients if only very mild disease is present. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Sulfasalazine' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Hydroxychloroquine' and "Rheumatoid arthritis and pregnancy".)
Rationale for DMARDs in UA — The decision to start DMARD therapy in patients with UA using a csDMARD such as MTX or SSZ represents a balancing of the risk of the disease and consequent benefit of early treatment with the risks of overtreatment. This approach is supported by 2013 and 2015 systematic reviews of drug therapy in UA that identified several randomized trials, open-label studies, and cohort studies, most of which included a substantial number of patients with early RA, which taken together suggested that temporary treatment with MTX, combination DMARDs, glucocorticoids and other agents were more effective than placebo in suppressing disease activity and radiographic progression, although the degree of long-term benefit from early treatment was uncertain [1,107]. As examples:
●One randomized trial suggested that treatment with MTX, compared with placebo, in patients somewhat similar to those defined here as having UA, may delay but not prevent the development of RA [2]. This trial involved 110 patients who met the modified 1958 American Rheumatism Association (ARA, subsequently the ACR) classification criteria for probable RA, but did not meet the 1987 ACR classification criteria for RA [2]. Treatment with MTX (titrated from 15 mg up to a maximum of 30 mg weekly in patients with a DAS >2.4) for 12 months resulted in a significantly smaller proportion of patients being diagnosed with RA (by the 1987 criteria) during the initial 12-month treatment phase of the trial and during 18 months of further follow-up (40 versus 53 percent). Additionally, treatment with MTX delayed the evolution to RA (by the 1987 criteria), as half of the MTX-treated patients diagnosed with RA did not meet classification criteria for RA during the first year, while all the patients receiving placebo who were diagnosed with RA met the criteria during that year. MTX-treated patients also exhibited less radiographic progression. However, later in the course of the disease there were neither major clinical nor radiographic differences between UA patients treated with MTX or placebo early on [108].
Estimates in the subgroup analysis of ACPA-positive and -negative patients were very imprecise, given the small numbers of patients in each group, but showed statistically significant benefits of MTX treatment only in the ACPA-positive subgroup, providing some support for our approach of using an alternative agent to MTX, such as SSZ, in ACPA-negative patients without clinical findings more suggestive of RA.
●One small trial lends some support to the hypothesis that intensive induction therapy in patients with early UA may lead to a cure, in this case for approximately 25 percent of patients [14]. This randomized trial involving 90 patients with UA of 12 weeks' duration compared induction therapy with MTX plus the TNF inhibitor infliximab (IFX), MTX, and placebo, followed by stopping treatment after clinical remission (by stringent criteria) was achieved. At one year, there was a higher rate of remission with MTX plus IFX compared with placebo, although the difference between MTX alone and placebo did not reach statistical significance (32 and 14 versus 0 percent, respectively). Among those who achieved remission, persistence of the remission after another year was substantially more common in the patients treated with MTX plus IFX compared with those receiving MTX monotherapy (75 versus 20 percent). Serious adverse events did not differ significantly between groups.
●Another trial involving 81 patients with both ACPA and RF positivity and arthralgia but no evidence of joint swelling, compared treatment with rituximab and placebo, finding a delay in the development of frank arthritis (joint swelling) but not the prevention of arthritis occurrence by 36 weeks [15]. Serious adverse events were significantly more frequent in the rituximab group. These results are consistent with those of the PROMPT study, which had used MTX as the intervention [2].
Additionally, data from randomized trials and other studies support the long-term benefits of early intervention with DMARDs in limiting progression of disease in patients with RA, further supporting the likely benefit of these approaches in UA [109] (see "General principles and overview of management of rheumatoid arthritis in adults", section on 'Early use of DMARDs'). In RA, a delayed start of DMARDs increases the risk of joint damage, which is irreversible, and the risk of disability [110,111].
Moreover, the underlying immunologic profile (the pattern of cell types and cytokines found in the synovial membrane) may differ in very early RA from that in later stages of disease [112,113]; a window of opportunity related to these immune characteristics may exist even in UA, given that UA may constitute an early state of RA in a considerable number of patients. During this period, treatment could be more effective than if it were delayed, resulting in a greater possibility of a biologic-free (and occasionally traditional DMARD-free) remission [13,114-117]. Further, the risk of inadequately controlled arthritis also includes systemic effects, such as future cardiovascular disease and osteoporosis, which may be fostered and aggravated by the inflammatory state [8,118,119], particularly in patients with positive testing for RF [120,121].
Further efforts at prevention may need to focus on a stage at which neither clinical signs nor symptoms are yet present, which might be achieved by screening the population or people at risk, such as first-degree relatives of known patients [122].
The risks of MTX, especially with folate substitution, or SSZ are generally modest, and their adverse effects are well recognized, with many decades of experience in the use of these agents and in the monitoring, prevention, and management of their risks (see "Major side effects of low-dose methotrexate" and "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis", section on 'Adverse effects' and "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis", section on 'Desensitization'). Most side effects are recognized and managed easily when patients are well-informed and regularly monitored (see 'Monitoring' below). Interestingly, it is rare to see new adverse events occurring after three months of therapy, unless doses are changed or other comorbidities develop [123]. Importantly, the risks of NSAIDs alone may be substantial, including gastrointestinal and cardiovascular risk, and the risk of adverse effects on renal function. (See "Nonselective NSAIDs: Overview of adverse effects".)
Additional benefits of effective csDMARD therapy in RA may also include a reduction in cardiovascular risk [124-126]. While good outcomes can also be achieved with biologic agents, we regard initiating DMARD therapy with biologics as overtreatment for UA, since many patients will fare well on csDMARDs combined with glucocorticoids even in established RA [127-130]; we reserve the use of such agents, as in RA, for patients with an inadequate response to initial therapies, especially those with an elevated risk of joint damage [88] (see 'Resistant to initial therapy' below). Of note, no bDMARD has shown superiority to the combination of MTX plus short-term glucocorticoids in RA [128,131]. We also usually do not combine synthetic DMARDs at the start of therapy, since these have not been unequivocally shown to be superior to monotherapy in this population or at this time point [105,132], and it is usually the glucocorticoid component that conveys the primary added benefit in most studies of initial combination therapy [133-136].
Resistant to initial therapy — In patients resistant to initial therapy, defined as failure to achieve either a 50 percent reduction in disease activity after three months of DMARD therapy, or low disease activity or remission after six months of such treatment (see 'Therapeutic target' above), the choice of DMARD therapy is based upon which medications have already been tried, the serologic findings, and the level of disease activity. Most patients should also be treated with NSAIDs and/or low-dose glucocorticoids to help control disease activity temporarily until the DMARDs are effective. (See 'Adjunctive role of antiinflammatory agents' below.)
In patients with UA resistant to initial therapies, we generally take one of the following approaches, depending upon the treatment history, the presence of RF or ACPA, and severity of disease activity:
●MTX resistant with upper extremity seronegative disease – In patients with upper-extremity disease but without RF or ACPA, who have had an inadequate response to MTX, we suggest sequential DMARD monotherapy with another agent (usually SSZ or LEF) or triple therapy with MTX, SSZ (up to 2000 mg daily), and HCQ. The dosing, adverse effects, and monitoring of HCQ are described in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease".)
In patients unable to take csDMARDs because of side effects, or those who have not experienced at least a 50 percent reduction in disease activity from baseline within three months (or remission or low disease activity within six months on a second csDMARD course), we would usually start a biologic agent or JAK inhibitor, whereas in RA, IL-6 receptor inhibitors and JAK inhibitors are more efficacious than a TNF inhibitor as monotherapies, although all bDMARDs have better efficacy in combination with csDMARDs. However, a trial of tofacitinib has provided evidence of an increased risk of cardiovascular events and malignancy compared with TNF inhibitors [137], and it is currently unknown to what extent this may also pertain to other JAK inhibitors.
This approach is based upon the generally good prognosis of patients with seronegative RA, particularly those with low disease activity, who are unlikely to develop severe joint destruction or rapid progression of damage [138,139]. For all these therapies, a similar goal for the treatment response would be sought: improvement within three months and remission or low disease activity at six months. If these goals are not met, the use of a bDMARD or a second bDMARD may be warranted. In seronegative patients with UA, we would prefer a TNF inhibitor or IL-17 inhibitor or IL-12/23 inhibitor over other biologics because of the proven efficacy of these agents in patients with PsA, and, except for IL-12/23 inhibition, also in ankylosing spondylitis.
●MTX resistant and RF or ACPA seropositive – In RF- or ACPA-positive patients without severe disease who have an inadequate response to MTX, we switch to a second csDMARD, such as LEF or SSZ, for an additional three to six months, or we step up to triple csDMARD therapy with MTX, SSZ, and HCQ. In RF- or ACPA-positive patients who have not achieved low disease activity or remission after a total of six months of DMARD monotherapy, we likewise switch to another csDMARD or step up to triple therapy, and in patients who do not achieve low disease activity or remission within three to six months on these therapies, we switch to MTX plus any of the bDMARDs that have proven effective in RA (usually a TNF inhibitor). (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)
●SSZ-resistant – In seronegative patients who have an inadequate response to SSZ (see 'Therapeutic target' above), we switch to MTX and also have a target of improvement after three months of MTX therapy and remission or low disease activity at six months.
●Sustained moderate to high disease activity – In the very infrequent patient with UA who does not meet treatment goals of low disease activity or remission despite at least six months of therapy with csDMARDs and has adverse prognostic features (eg, positive test for RF or ACPA, or high levels of disease activity) we treat with the combination of MTX and a TNF inhibitor, using the same approach and regimens used in RA. Alternatively, other biologics or a JAK inhibitor may also be used. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Resistant to methotrexate'.)
We generally avoid starting with bDMARDs because we would risk overtreatment of a large proportion of patients. Use of these agents is generally not required because of the typically mild disease seen in these patients. Trials in early RA comparing csDMARDs and glucocorticoids (even at low doses) with the combination of a csDMARD with a bDMARD have not revealed any major differences in outcomes [127,128,131,140]. An additional concern with the use of TNF inhibitors is their somewhat higher risk of infections and other adverse effects. In patients with dactylitis or enthesitis, suggesting a SpA, TNF, IL-12/23, or IL-17 inhibitors would be the preferred drug after NSAID failure, but usually such patients could be categorized as having a SpA rather than UA and would be treated following the approach established for SpA. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Resistant to methotrexate' and "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'TNF inhibitors' and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases" and "Treatment of peripheral spondyloarthritis".)
Adjunctive role of antiinflammatory agents — We use antiinflammatory therapies, including systemic and intraarticular glucocorticoids and NSAIDs, primarily as adjuncts for temporary control of disease activity in patients in whom treatment is being started with csDMARDs, in patients in whom the csDMARD regimen requires modification, or in patients who are experiencing disease flares. Although NSAIDs and/or glucocorticoids act rapidly to control inflammation in UA or RA, they do not provide adequate benefit on their own for longer-term control of disease or for prevention of joint injury. More detailed discussions of NSAIDs and glucocorticoids in RA are presented elsewhere. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "Initial treatment of rheumatoid arthritis in adults", section on 'Symptomatic treatment with antiinflammatory drugs'.)
Drug therapy for flares — Patients with UA, like those with RA, may experience natural exacerbations of disease activity (also known as flares) and natural reductions in disease activity. We approach the evaluation and management of disease exacerbations in patients with UA the same as in RA, as described separately. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug therapy for flares'.)
MONITORING — We perform monitoring of disease activity and for drug toxicity using the same approach as for patients with rheumatoid arthritis (RA), which is described in detail separately. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Assessment and monitoring'.)
PROGNOSIS — The prognosis of undifferentiated early inflammatory arthritis has been examined in several studies of cohorts of patients with early arthritis, but the definitions of "early," the duration of follow-up, and the types of patients included in the cohorts has varied; however, the condition remained undifferentiated in 21 to 87 percent of the patients with the baseline diagnosis of UA in these early arthritis cohort studies after one year of follow-up, and rheumatoid arthritis (RA) was diagnosed in 13 to 55 percent of patients with undifferentiated arthritis (UA) at initial evaluation during the year [18]. Osteoarthritis was diagnosed during follow-up of patients with UA at baseline in 0 to 16 percent, and other forms of arthritis were diagnosed in 6 to 20 percent.
Approximately 10 to 40 percent of patients with any type of early arthritis experienced spontaneous remission within one year [18]; this proportion was not increased by treatment with glucocorticoids [83,141]. In one study with a two-year follow-up of UA, a diagnosis of RA was made in 30 percent during the follow-up period, arthritis resolved in 41 percent, and 10 percent were lost to follow-up [142]. In another study, spontaneous remission of arthritis was rare once symptoms exceeded eight weeks in duration [83].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Undifferentiated early inflammatory arthritis".)
SUMMARY AND RECOMMENDATIONS
●Undifferentiated arthritis (UA) is a diagnosis of exclusion made in patients with inflammatory arthritis who have at least one clinically swollen joint, in the absence of further findings on a thorough evaluation that allow for making a diagnosis of another specific rheumatologic disease (see 'Diagnostic evaluation' above). A complaint of arthralgia in the absence of a swollen joint on examination or findings such as pain on motion or tenderness upon pressure is not sufficient to make a diagnosis of UA. (See 'Definition and clinical features' above.)
●Patients with UA require effective treatment to begin to alleviate symptoms and to alleviate and prevent the functional impairment associated with active disease. Thus, patients with an undetermined form of inflammatory arthritis following initial evaluation should be referred for an initial consultation with an expert in rheumatologic disease as soon as possible to assist in making a diagnosis, when feasible, and developing a treatment plan. Many of the patients with UA after the initial evaluation will eventually be able to be diagnosed with rheumatoid arthritis (RA) with further evolution of the symptoms and findings. (See 'Introduction' above and 'Epidemiology and natural history' above and 'When to refer' above.)
●Patients determined to have UA typically have symptoms that have lasted from several weeks to months at time of presentation; morning stiffness most often for less than a half hour to an hour, but sometimes longer; less than four swollen joints; arthritis affecting the upper extremities, mostly affecting the hands, more often than the lower extremities; and normal to only modestly elevated levels of acute phase reactants. Rheumatoid factor (RF) and/or anti-citrullinated peptide antibodies (ACPA) are each positive in approximately 10 percent of patients. (See 'Definition and clinical features' above.)
●The diagnostic evaluation includes a medical history, physical examination, and laboratory and imaging studies to confirm the presence of arthritis and to exclude other disorders. Such exclusionary findings may include a history and/or findings on examination of extraarticular features that suggest another diagnosis; arthrocentesis that facilitates the recognition of an infectious or crystal arthritis; and imaging studies with abnormal findings that are characteristic of particular arthritic disorders. (See 'Diagnostic evaluation' above and 'Differential diagnosis' above.)
●In patients with UA, we suggest initial treatment with a conventional synthetic disease-modifying antirheumatic drug (csDMARD), rather than only nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids (Grade 2B). The initial therapeutic goal is to achieve significant clinical improvement within three months, which may be defined as at least a moderate (50 percent) reduction in disease activity using a composite measure. (See 'Treatment approach' above and 'Initial DMARD therapy' above and 'Therapeutic target' above and 'Rationale for DMARDs in UA' above.)
●In patients with UA with upper-extremity involvement or who have a positive test for RF or ACPA, we suggest methotrexate (MTX) rather than other DMARDs (Grade 2C). The dose should be gradually titrated up to 20 to 25 mg once weekly to achieve a clinical response. (See 'Upper extremity disease or RF/ACPA-positive' above.)
●In patients with UA who lack RF or ACPA and have involvement primarily of the lower extremities, we suggest initiating DMARD therapy with sulfasalazine (SSZ) rather than other DMARDs (Grade 2C). The dose should be gradually increased up to 1.5 grams twice daily to achieve a clinical response. (See 'Seronegative lower extremity predominance' above.)
●Treatment of patients who are resistant to initial therapy at three months or do not achieve remission or low disease activity after six months of therapy is based upon which medications have been tried and the response to those agents, with the same therapeutic targets as for initial therapy. In patients who have not responded adequately to initial DMARD therapy, we prefer another DMARD monotherapy rather than combination therapy with MTX, SSZ, and hydroxychloroquine (HCQ) or initiating treatment with a biologic DMARD (bDMARD). (See 'Resistant to initial therapy' above.)
●We generally limit the use of a bDMARD (eg, a tumor necrosis factor [TNF] inhibitor administered as in RA or PsA or an IL-12/23 or IL-17 inhibitor as is administered in PsA) to patients with UA who have failed at least six months of initial csDMARD therapies and have adverse prognostic features such as high disease activity, positive tests for RF or ACPA, as typical for RA, or joint damage (eg, erosions, joint space narrowing). (See 'Resistant to initial therapy' above.)
●We use antiinflammatory therapies, including systemic and intraarticular glucocorticoids and NSAIDs, primarily as adjuncts for temporary control of disease activity in patients in whom treatment is being started with DMARDs, in patients in whom the DMARD regimen requires modification, or in patients who are experiencing disease flares. (See 'Adjunctive role of antiinflammatory agents' above and 'Drug therapy for flares' above.)
●The approaches to preventive and nonpharmacologic therapy, pretreatment evaluation, and monitoring of disease activity and for drug toxicity follow the same strategies as for patients with RA. (See 'Treatment' above and 'Pretreatment evaluation' above and 'Monitoring' above.)
