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Undifferentiated inflammatory arthritis in adults

Undifferentiated inflammatory arthritis in adults
Literature review current through: Jan 2024.
This topic last updated: Jan 08, 2024.

INTRODUCTION — The terms "undifferentiated arthritis" and "undifferentiated inflammatory arthritis" (UA) are used to describe patients with inflammatory arthritis that has not differentiated into a specific rheumatic disease, such as rheumatoid arthritis (RA) or psoriatic arthritis (PsA).

UA is most frequently used to describe patients during the first weeks to months following symptom onset, when it may not be possible to establish a specific diagnosis. However, UA also describes patients who fail to differentiate into another rheumatic disease, even after prolonged follow-up.

Patients with UA must often start therapy before it is clear whether their disease will evolve into another diagnosis, resolve spontaneously, or remain undifferentiated. Early treatment must be initiated to alleviate symptoms and to prevent the development of functional impairment caused by an untreated inflammatory arthritis [1-9].

The evaluation and management of patients with UA will be presented in this topic. The evaluation of patients with monoarticular and polyarticular pain and specific rheumatic diseases associated with an inflammatory arthritis are described in detail separately:

(See "Monoarthritis in adults: Etiology and evaluation".)

(See "Evaluation of the adult with polyarticular pain".)

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

(See "Clinical manifestations and diagnosis of peripheral spondyloarthritis in adults".)

(See "Clinical manifestations and diagnosis of psoriatic arthritis".)

EPIDEMIOLOGY

Prevalence – An undifferentiated arthritis (UA) is present in approximately a quarter to a third of patients presenting with an early arthritis (ie, less than two to three months of symptoms) [10-12].

Incidence – The incidence of UA ranges from 41 to 149 per 100,000 adults [10].

CLINICAL AND LABORATORY FEATURES — Undifferentiated arthritis (UA) is not a single disorder. UA encompasses patients who do not meet criteria for another inflammatory arthritis. Therefore, there are no clinical, laboratory, or radiographic features that are found in all patients with UA.

The clinical and laboratory features associated with UA were described in a cohort of 776 patients prospectively evaluated in an early arthritis clinic in the Netherlands [13]:

Morning stiffness – Morning stiffness lasted for less than an hour in 46 percent of patients (median of 30 minutes, interquartile range [IQR] 0 to 60 minutes).

Swollen joint count – Most patients (65 percent) had fewer than four swollen joints. Only 6 percent of patients had more than 10 swollen joints.

Joint distribution – Arthritis affected the upper extremities (especially the hands) in 76 percent of patients, and 48 percent had symmetric joint involvement.

Acute phase reactants – Half of patients had normal acute phase reactants (ie, C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]). The median ESR was 16 mm/h (IQR 8 to 36 mm/h) and the median CRP was 8 mg/L (IQR 3 to 23 mg/L).

Autoantibodies – Rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA) were each present in 10 percent of patients.

A second study of 310 patients with UA from the Netherlands examined the one-year outcomes among patients with UA who lacked autoantibodies. This study determined that patients with UA fell into one of five clinical presentations [14]:

Polyarthritis (ie, more than four swollen joints) – 20 percent of cohort patients

Oligoarthritis (ie, two to four swollen joints) – 43 percent of cohort patients

Wrist monoarthritis – 9 percent of cohort patients

Large-joint monoarthritis (eg, hip, shoulder, knee) – 18 percent of cohort patients

Small-joint monoarthritis (eg, hands, feet) – 29 percent of cohort patients

However, the meaning of UA has continued to evolve with time. With this evolution, the clinical features associated with this diagnosis have also changed; in particular, patients with UA now have milder disease than had been reported previously.

Many patients who previously would have been diagnosed as having UA are now diagnosed as having rheumatoid arthritis (RA) [11]. This has been particularly true following the publication of the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for RA, which were developed to capture patients with early forms of RA [15].

DIAGNOSTIC EVALUATION — Undifferentiated arthritis (UA) is a diagnosis of exclusion. Therefore, the bulk of the diagnostic evaluation focuses on excluding other causes of inflammatory arthritis.

Identification of inflammatory arthritis — The first step towards diagnosing UA is to establish the presence of an inflammatory arthritis consistent with UA. This requires the detection of clinical joint swelling.

Clinical joint swelling can generally be identified with a musculoskeletal examination alone. However, imaging can be helpful to confirm equivocal examination findings.

Confirm presence of clinical joint swelling — We perform a musculoskeletal examination to confirm the presence of clinical swelling in at least one joint, which is the minimum necessary to be diagnosed with UA.

Clinical joint swelling caused by synovitis is characterized by soft tissue swelling along the joint margins; it is often warm and tender to palpation, and a joint effusion may be present.

UA cannot be diagnosed in a patient without clinical joint swelling, which indicates the presence of synovitis. Joint pain, joint tenderness, and imaging abnormalities (in the absence of clinical joint swelling) are not sufficient to diagnose UA.

The musculoskeletal examination in a patient presenting with joint pain is described in detail elsewhere. (See "Evaluation of the adult with polyarticular pain", section on 'Joint examination'.)

Limited role for imaging to confirm synovitis — In some patients, joint swelling due to synovitis may be difficult to distinguish from joint swelling due to other causes (eg, fat, edema). In these cases, we use ultrasound of the affected joint to confirm the presence of synovitis. Magnetic resonance imaging (MRI) is a reasonable alternative when ultrasound is not available.

Comparing modalities – Both ultrasound and MRI may be helpful for confirming the presence of synovitis [16-18]. However, we prefer to use ultrasound for this purpose, given its low cost and availability compared with MRI. The use of ultrasound and MRI for the evaluation of inflammatory arthritis are discussed elsewhere. (See "Imaging techniques for evaluation of the painful joint", section on 'Magnetic resonance imaging' and "Musculoskeletal ultrasonography: Clinical applications", section on 'Joints'.)

Imaging alone is inadequate to diagnose UA – We do not use ultrasound or MRI alone to make a diagnosis of UA in the absence of clinical joint swelling. The specificity of ultrasound or MRI findings for UA in the absence of clinical disease is not clear [19]. Some observations regarding the lack of specificity of ultrasound or MRI for inflammatory arthritis include the following:

Ultrasound of healthy, normal joints may demonstrate abnormalities consistent with an inflammatory arthritis, including power Doppler signals [20].

MRI of healthy, normal joints may demonstrate transient evidence of inflammation and erosions in up to 70 percent of people [21,22].

MRI frequently detects erosive disease in patients with systemic lupus erythematosus (SLE) and Sjögren's disease, two diseases not typically associated with joint erosions, raising further questions regarding the specificity of such MRI findings [23,24].

Exclusion of other disorders — After the presence of an inflammatory arthritis has been confirmed, alternate causes of inflammatory arthritis must be excluded. (See 'Differential diagnosis' below.)

Most of these other disorders can be readily distinguished from UA by using the following approach:

Identify extraarticular features — UA is not associated with extraarticular features, other than constitutional symptoms. Therefore, a thorough history and physical examination should be obtained to determine if there is evidence of extraarticular disease, which may point to an alternative diagnosis (table 1). For example, the presence of psoriasis should raise suspicion for a diagnosis of psoriatic arthritis (PsA).

The approach to evaluating a patient with inflammatory arthritis for extraarticular features is very similar to the approach used when evaluating a patient for rheumatoid arthritis (RA), which is discussed in detail separately. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Differential diagnosis'.)

Plain radiographs for all patients — All patients should have plain radiographs of the affected joints and the contralateral joints (for comparison). Patients with arthritis affecting the hands should have plain radiographs of both hands and feet, both to establish the baseline appearance of the joints and to evaluate for changes indicative of other forms of inflammatory arthritis [25].

To evaluate for rheumatoid arthritis – Plain radiography is particularly useful to identify joint erosions consistent with RA [25,26]. For example, erosions affecting the metacarpophalangeal joints are characteristic of RA but not UA. Patients with early RA may exhibit erosive changes in the feet even in the absence of symptoms.

Erosions are found in almost 10 percent of patients with very early RA, but they are less common in patients with UA [27].

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 with RA in the near future [28].

To evaluate for other forms of arthritis – Other forms of inflammatory arthritis (eg, PsA, gout) are also associated with characteristic changes that may be detected on plain radiographs, but these are less likely to appear early in the disease course. However, early osteoarthritis can be diagnosed using plain radiography.

The use of plain radiography to diagnose other forms of arthritis is discussed elsewhere:

(See "Clinical manifestations of rheumatoid arthritis", section on 'Plain film radiography'.)

(See "Clinical manifestations and diagnosis of psoriatic arthritis", section on 'Imaging findings'.)

(See "Clinical manifestations and diagnosis of gout", section on 'Imaging'.)

(See "Clinical manifestations and diagnosis of osteoarthritis", section on 'Imaging'.)

Arthrocentesis in patients with large joint involvement — We perform arthrocentesis in any patient presenting with an acute arthritis affecting the large joints (eg, knees or shoulders) or the wrist to exclude diagnoses such as infectious arthritis or crystal disease.

Testing should include a cell count, differential, Gram stain, and culture. The synovial fluid should also be carefully examined for evidence of crystals indicative of a crystalline arthritis (eg, gout, pseudogout). (See "Monoarthritis in adults: Etiology and evaluation", section on 'Joint aspiration'.)

Review family history — We obtain a family history to identify a family history of disease associated with inflammatory arthritis, such as:

Ankylosing spondylitis

Systemic rheumatic disease (eg, SLE)

Psoriasis

Inflammatory bowel disease

RA

A family history of any of these disorders should prompt a more detailed history and laboratory evaluation to look for evidence of the same disorder in the patient. However, lack of a family history of any of these disorders does not exclude the diagnosis of UA.

The evaluation of these diagnoses is discussed in detail in other topic reviews.

Limited role for additional laboratory testing — We obtain laboratory tests especially when there is clinical evidence of another disorder (table 2). This approach is very similar to the approach used to evaluate the differential diagnosis of RA, which is discussed in detail separately. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Differential diagnosis'.)

As an example, patients with a family history of SLE or symptoms related to SLE (eg, photosensitive rash) should undergo additional laboratory testing to exclude SLE as a cause of arthritis. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Laboratory testing'.)

In the absence of clinical features of another rheumatic or inflammatory diagnosis, general screening tests are unhelpful. The evaluation of patients with clinical features of another diagnosis is discussed below. (See 'Differential diagnosis' below.)

Laboratory testing required prior to the initiation of pharmacotherapy is discussed below. (See 'Pretreatment evaluation' below.)

DIFFERENTIAL DIAGNOSIS — Many diagnoses, including undifferentiated arthritis (UA), are characterized by the presence of synovitis. With some exceptions, UA can be distinguished from alternate diagnoses with a thorough history, physical examination, and selected testing. (See "Monoarthritis in adults: Etiology and evaluation" and "Evaluation of the adult with polyarticular pain" and "Viral arthritis: Causes and approach to evaluation and management", section on 'Evaluation and diagnosis'.)

Rheumatoid arthritis – Rheumatoid arthritis (RA) is the principal diagnosis that should be considered in patients who appear to have UA. In its early stages, RA may not be distinguishable from UA for the following reasons (see "Clinical manifestations of rheumatoid arthritis"):

Patients with early RA may not have developed the symmetric pattern of joint involvement that is characteristic of this disease.

Patients with RA may lack rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) (seronegative RA).

Patients with early RA generally lack joint damage or extraarticular manifestations

The diagnosis of RA may become clear over time if the patient develops joint damage, extraarticular manifestations, characteristic autoantibodies (RF, ACPA) or a pattern of joint involvement characteristic of RA. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)

Because the initial treatment approach to UA and RA are similar, differentiating between these two diagnoses when initiating pharmacotherapy may not be crucial for most patients. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Pharmacologic therapy'.)

Other causes of arthritis – Other disorders that may appear to represent UA include viral arthritis, which is self-limited; psoriatic arthritis (PsA); undifferentiated spondyloarthritis (SpA); or sarcoidosis as well as the wide range of conditions associated with inflammatory arthritis, such as systemic lupus erythematosus (SLE) (table 2).

The approach to the differential diagnosis of UA is very similar to the approach used for the differential diagnosis of RA, which is discussed in detail separately. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Differential diagnosis'.)

TREATMENT

General principles — Our overall approach to the treatment of undifferentiated arthritis (UA) is guided by the following principles:

Early treatment for all patients — The goal of early therapy is to suppress of inflammation and the prevention of persistent or recurrent inflammation and irreversible joint damage [1-6,29-33].

This goal is best accomplished by initiating treatment with a disease-modifying antirheumatic drug (DMARD) as soon as an inflammatory arthritis is detected.

The immunology underlying early UA may differ substantially from the immunology of chronic UA [34]. Some patients may be more responsive to immunosuppression earlier in their disease course, and patients who are treated early are more likely to experience a complete remission. (See 'Rationale for csDMARDs in undifferentiated arthritis' below.)

Specialty referral for all patients — We suggest referring all patients with UA to a rheumatologist. Patients with arthritis receive better care when assessed and treated by rheumatologists than generalists, both in terms of an earlier specific diagnosis and better outcomes [35-39].

Multidisciplinary and nonpharmacologic management — 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 for patients with UA are the same as those used for the treatment of rheumatoid arthritis (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".)

Pretreatment evaluation — Prior to initiating pharmacotherapy, we obtain the following tests:

Complete blood count, blood urea nitrogen, creatinine, and aminotransferases may help to monitor for adverse reactions to the pharmacotherapy of UA (see 'Monitoring and treatment duration' below)

Acute phase reactants (ie, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]) may be used to help track response to pharmacotherapy by demonstrating declining levels of systemic inflammation (see 'Monitoring and treatment duration' below)

Rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA) may assist with the selection of pharmacotherapy (see 'Initial therapy' below and 'Resistant to initial therapy' below)

All patients should also have plain radiographs of the affected joints, which can be useful for tracking the presence of joint damage over time. (See 'Plain radiographs for all patients' above.)

Other assessments that should be completed prior to starting or resuming therapy with a conventional synthetic DMARD (csDMARD), or intensifying treatment with use of a biologic DMARD (bDMARD), are discussed in the table (table 3). Our approach to the pretreatment evaluation of patients with UA is similar to the approach used for RA. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Pretreatment evaluation'.)

Initial therapy

Regimen selection — In patients with UA, we suggest treatment with glucocorticoids and a csDMARD.

csDMARD — For most patients, we suggest methotrexate (MTX). However, we use sulfasalazine (SSZ) for patients who may become pregnant and patients with predominantly lower-extremity involvement who lack RF/ACPA. Alternative therapies to MTX and SSZ include hydroxychloroquine (HCQ) and leflunomide (LEF).

Methotrexate for most patients - For most patients, we suggest MTX.

MTX is administered weekly, either orally or subcutaneously. Patients should start at 15 mg weekly, and the dose should be increased over the subsequent month to 20 to 25 mg weekly, using the same approach used for patients with RA.

As in RA, MTX therapy should be accompanied by daily folate supplementation (eg, folate 1 mg orally) to prevent side effects.

Further details regarding the dosing and administration of MTX are discussed elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

We use MTX for most patients because it is widely available, well tolerated, and effective for a broad range of inflammatory arthritides, including RA, which is the most common diagnosis that patients with UA will receive (if they differentiate into another diagnosis). Moreover, MTX has been studied more closely for the treatment of UA than other DMARDs. (See 'Rationale for csDMARDs in undifferentiated arthritis' below.)

Sulfasalazine for seronegative lower extremity involvement or pregnancy – We use SSZ for patients who decline MTX or may become pregnant [40]. We also use SSZ for patients with predominantly lower-extremity involvement who lack RF/ACPA. The starting dose is 500 mg twice daily, and the dose should be gradually increased over the subsequent month to a maximum of 1500 mg twice daily.

In patients who experience gastrointestinal intolerance, SSZ may be administered three times daily instead of twice daily. This is the same approach used for the treatment of RA and peripheral spondyloarthritis (SpA).

The dosing and administration of SSZ is discussed elsewhere. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis", section on 'Dosing and monitoring'.)

We use SSZ for patients with lower-extremity involvement because of the increased likelihood that they will evolve into an SpA, for which SSZ (but not MTX) is effective. SSZ is also effective for the treatment of RA and, unlike MTX, is safe for both pregnancy and lactation. We prefer MTX for patients who have RF/ACPA, since they are more likely to evolve to RA, for which MTX is first-line therapy. (See 'Rationale for csDMARDs in undifferentiated arthritis' below and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Sulfasalazine'.)

We usually do not combine csDMARDs at the start of therapy, since these have not been unequivocally shown to be superior to monotherapy in this population [41,42].

Alternative csDMARDs – We do not use a bDMARD for initial therapy of UA. (See 'Avoiding bDMARDs for initial therapy' below.)

There are no studies demonstrating which agent (or combinations of agents) is most effective for UA.

Hydroxychloroquine – HCQ is an alternative for patients with very mild disease activity who are RF- and ACPA-negative but clinically resemble RA more than SpA (eg, patients who have predominantly upper-extremity joint involvement).

In patients who are close to achieving remission or low disease activity with MTX, we add HCQ rather than transitioning to a new agent.

Dosing and monitoring of HCQ is discussed elsewhere. (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'.)

Leflunomide – LEF is an alternative for patients with UA, based on experience using this drug for both RA and psoriatic arthritis (PsA).

In patients who have had a partial response to MTX, it would be reasonable to add LEF rather than transitioning to a new agent. However, there is an increased risk of transaminitis associated with this approach. Therefore, transitioning to a new agent (eg, a biologic agent) may be associated with fewer complications than using LEF and MTX in combination. (See 'Resistant to initial therapy' below.)

Dosing and monitoring of LEF is discussed elsewhere. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Leflunomide'.)

Plus low-dose glucocorticoids — We treat with low-dose prednisone for a limited period of time to help achieve disease control (ie, 5 mg daily or less for no more than three months or a single intramuscular injection of glucocorticoids [eg, triamcinolone acetate 40 to 60 mg]). In studies evaluating initial combination therapy, adding glucocorticoids to DMARDs leads to a long-term reduction in radiographic damage and disease activity [43-46].

The approach to using glucocorticoids for UA is very similar to the approach used for the treatment of RA, which is discussed extensively elsewhere. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis", section on 'Efficacy of short-term use'.)

Treatment goals — The therapeutic goal of treatment in the first three months is clinical improvement; the therapeutic goal of treatment for next three months (and beyond) is to attain remission or low disease activity:

Clinical improvement in the first three months – The initial therapeutic goal is to achieve significant clinical improvement within three months of treatment, 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).

Both the SDAI and CDAI create a numerical representation of disease activity based on the total number of tender and swollen joints and global assessments of disease activity (by the patient and an objective evaluator). The SDAI also incorporates the CRP. Formulas for both the SDAI and CDAI are presented elsewhere. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Clinical Disease Activity Index (CDAI)' and "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Simplified Disease Activity Index (SDAI)'.)

Remission/low disease activity in the next three months – The goal of continued therapy is to attain remission or low disease activity within the subsequent three months and to maintain remission or low disease activity thereafter.

Remission is defined according to the American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) revised definition of remission for patients with RA [47-50]. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'Criteria for remission'.)

This approach to the treatment goals for UA is based on:

Clinical experience in patients with UA [1-3,51-58] (see 'Rationale for csDMARDs in undifferentiated arthritis' below)

Evidence supporting this strategy in patients with RA, consistent with EULAR RA management recommendations [59] (see "General principles and overview of management of rheumatoid arthritis in adults", section on 'Tight control')

Expert opinion and indirect evidence supporting a similar treat-to-target approach for SpA and PsA (see "Treatment of peripheral spondyloarthritis", section on 'Prognosis' and "Treatment of psoriatic arthritis", section on 'Monitoring')

Rationale for csDMARDs in undifferentiated arthritis — The decision to start DMARD therapy in patients with UA using a csDMARD such as MTX or SSZ requires balancing of the benefits of early treatment given the risks of untreated disease against the risks of treatment and overtreatment. However, for most patients, the benefits to early treatment outweigh the risks.

Benefits of early immunosuppression

Improved outcomes – Systematic reviews of drug therapy in UA suggest that early immunosuppression is more effective than placebo at suppressing disease activity and radiographic progression [1,11].

An observational study of 335 patients with inflammatory arthritis made the following observations [60]:

-Overall, patients who were treated with DMARDs had higher level of joint damage than patients who were not treated. This likely reflects that patients who received immunosuppression had greater disease severity at baseline.

-After adjusting for the greater disease severity among patients receiving DMARD therapy, patients who started treatment within six months of symptom onset had less joint damage after five years than patients who received treatment at later timepoints.

Mitigating evolution to rheumatoid arthritis – Early treatment may not prevent UA from evolving to RA. However, early treatment may delay the onset of RA and may reduce the overall functional impairment experienced by such patients [61,62].

In one study, 236 patients with preclinical RA (ie, arthralgias and subclinical joint inflammation) were randomized to receive treatment with oral MTX (up to 25 mg/week) and a single intramuscular glucocorticoid injection (120 mg depot methylprednisolone) or placebo [62]. After two years of follow-up, equal numbers of patients in both groups developed RA. However, patients treated with MTX had sustained improvements in physical function, pain, morning stiffness and MRI-detected joint inflammation when compared with patients treated with placebo.

In RA, the underlying immunologic profile (the pattern of cell types and cytokines found in the synovial membrane) of early disease differs from late disease [63,64]. Also, differences in deoxyribonucleic acid (DNA)-methylation status have been noted in UA patients who progress to RA [65]. 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 DMARD-free remission [66-70].

Risks of untreated disease – 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 [30,71,72], particularly in patients with positive testing for RF [73,74].

Modest risks of immunosuppression – 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 managed easily when patients are well informed and monitored regularly. (See 'Monitoring and treatment duration' below.)

It is rare to see new adverse events occurring after three months of therapy, unless doses are changed or other comorbidities develop [75].

Avoiding bDMARDs for initial therapy — We generally avoid starting with bDMARDs because we would risk overtreatment of a large proportion of patients. Moreover, use of these agents is generally not required because of the typically mild disease seen in these patients.

Most trials in early RA comparing csDMARDs and glucocorticoids (even at low doses) versus the combination of a csDMARD and a bDMARD have not revealed any major differences in outcomes [76-79]. An additional concern with the use of tumor necrosis factor (TNF) inhibitors is their somewhat higher risk of infections and other adverse effects. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Adverse effects'.)

Resistant to initial therapy

Definition of treatment resistance – We define treatment resistance using one of the two following criteria (see 'Treatment goals' above):

Failure to achieve a 50 percent reduction in disease activity after three months of DMARD therapy

Failure to achieve low disease activity or remission after six months of DMARD therapy

Selecting the treatment approach – In patients with UA resistant to initial therapies, the approach depends on the regimen used for initial therapy:

Methotrexate resistant – In patients who have had an inadequate response to MTX, we add or transition to monotherapy with a biologic agent.

Resistant to csDMARD other than methotrexate – In patients who have an inadequate response to a csDMARD other than MTX (eg, SSZ, LEF, HCQ), we switch to MTX. It would be reasonable to switch to monotherapy with a biologic agent if the patient has contraindications for MTX.

Adjunctive antiinflammatory – We also treat most patients with nonsteroidal antiinflammatory drugs (NSAIDs) and/or short-term (<3 months) glucocorticoids to help control disease activity temporarily until the DMARDs are effective. (See 'Adjunctive role of antiinflammatory agents' below.)

Selecting a biologic agent

Tumor necrosis factor inhibitors for most methotrexate-resistant patients — In patients with UA who require treatment with a biologic agent, we generally select a TNF inhibitor. Starting doses are the same as those used in RA. We suggest the use of TNF inhibitors because of their low cost, wide availability, and therapeutic efficacy for multiple forms of inflammatory arthritis (eg, RA, PsA, ankylosing spondylitis). These data are discussed elsewhere in the appropriate topic reviews.

If treatment goals (ie, clinical improvement within three months and remission or low disease activity at six months) are not met with a TNF inhibitor, we transition to a different bDMARD, depending on disease characteristics.

One small trial lends some support to the hypothesis that treatment of UA with a TNF inhibitor may lead to cure for some patients [80]. In a study of 90 patients with UA, initial treatment with infliximab and MTX was associated with greater rates of drug-free remission than treatment with MTX alone (75 versus 20 percent). Despite this observation, we believe the bulk of the evidence continues to support using a csDMARD for the initial therapy of UA. (See 'Avoiding bDMARDs for initial therapy' above.)

Biologic selection for tumor necrosis factor inhibitor-resistant patients

-Interleukin 6 receptor or Janus kinase inhibitor – For patients who are expected to evolve towards RA (eg, RF-/ACPA-positive, predominantly upper-extremity joint disease, presence of tenosynovitis [81-85]), we would use an interleukin 6 (IL-6) or Janus kinase (JAK) inhibitor, based on their efficacy for RA. In RA studies, monotherapy with either an IL-6 or JAK inhibitor is more efficacious than TNF inhibitor monotherapy [86,87]. However, JAK inhibitors may be associated with an increased risk of cardiovascular events and malignancy and respective risk factors should be thoroughly evaluated.

Both IL-6 receptor and JAK inhibitors are discussed elsewhere. (See "Overview of biologic agents in the rheumatic diseases", section on 'IL-6 inhibition' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'JAK inhibitors'.)

-Interleukin 17 or interleukin 23 inhibitor – For patients who are expected to evolve towards a spondyloarthropathy (eg, RF-/ACPA-negative, predominantly lower extremity joint disease), we would use an IL-17 inhibitor based on its efficacy for ankylosing spondylitis and PsA.

Patients who are expected to evolve towards PsA (eg, patients with psoriasis) could also be treated with an IL-12/23 inhibitor (eg, ustekinumab) or IL-23 inhibitor (eg, guselkumab).

These agents are discussed elsewhere. (See "Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults", section on 'Interleukin 17 inhibitors' and "Treatment of peripheral psoriatic arthritis", section on 'Patients without concomitant axial disease'.)

Adjunctive role of antiinflammatory agents — We use antiinflammatory therapies, including systemic and intraarticular glucocorticoids and NSAIDs, primarily for temporary control of disease activity in patients who are starting/changing DMARDs and/or patients experiencing a disease flare.

However, the long-term use of both glucocorticoids and NSAIDs is associated with substantial side effects. Moreover, although NSAIDs act rapidly to reduce inflammation in UA or RA, they do not prevent joint damage. More detailed discussions of NSAIDs and glucocorticoids for the treatment of 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 disease flares. Our approach to the management of disease flares is the same as our approach in RA, which is described separately. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug therapy for flares'.)

MONITORING AND TREATMENT DURATION — We monitor disease activity and 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'.)

Our approach to the long-term therapy of undifferentiated arthritis (UA) is similar to the approach used for patients with RA. Notably, patients who have had UA for over one year are unlikely to remit spontaneously or evolve to another diagnosis, as discussed below. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Duration of therapy'.)

PROGNOSIS — Patients initially diagnosed with undifferentiated arthritis (UA) generally have one of three long-term outcomes:

Persistent undifferentiated arthritis – Approximately 21 to 87 percent of the patients initially diagnosed with UA will not differentiate into another diagnosis, even after one or two years of follow-up [7,8,10].

Differentiation to another diagnosis – Approximately 13 to 55 percent of patients initially diagnosed with UA will be rediagnosed with RA after one year of follow-up [8,10]. Another 6 to 20 percent of patients will be diagnosed with another form of inflammatory arthritis (eg, psoriatic arthritis [PsA]), and up to 16 percent will be diagnosed with osteoarthritis.

Patients with UA who present with a monoarthritis are the least likely to progress to RA. One study examined the one-year outcomes of 310 patients with UA who lacked rheumatoid factor (RF) or anti-citrullinated peptide antibodies (ACPA) [14]. After one year of follow-up, progression to RA was experienced by 2 percent of patients who presented with a monoarthritis, 10 percent of patients who presented with an oligoarthritis, and 21 percent of patients who presented with a polyarthritis.

If patients evolve from UA to a specific diagnosis, this will typically occur within a year of presentation. In such cases, the patient’s treatment regimen may need to be altered to reflect the patient’s new diagnosis (eg, RA, PsA). (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Pharmacologic therapy' and "Treatment of peripheral psoriatic arthritis".)

Resolution of the inflammatory arthritis – Some patients initially diagnosed with UA will experience complete resolution of their inflammatory arthritis, without pharmacotherapy, generally in the first few months following diagnosis.

The specific percent of patients with UA who experience spontaneous resolution of their disease is unknown. However, approximately 10 to 40 percent of patients with any type of early arthritis (many of whom have UA) will experience spontaneous resolution of their inflammatory arthritis within one year [10]. The use of glucocorticoids does not increase the rate of spontaneous resolution of UA [88,89].

Patients with UA who present with a monoarthritis are the most likely to experience spontaneous disease resolution. One study examined the one-year outcomes of 310 patients with UA who lacked RF or ACPA [14]. After one year of follow up, spontaneous resolution occurred in 72 percent of patients with UA who presented with a monoarthritis, 40 percent of patients who presented with an oligoarthritis, and 34 percent of patients who presented with a polyarthritis.

Patients with UA for longer than two to three months are unlikely to enter a spontaneous remission. In one study of very early inflammatory arthritis, patients who had more than eight weeks of symptoms were unlikely to experience spontaneous remission [88].

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

Definition – Undifferentiated arthritis (UA) is a diagnosis of exclusion. UA refers to patients who have at least one clinically swollen joint but do not meet criteria for an alternative diagnosis. Arthralgias in the absence of a clinically swollen joint are not sufficient to make a diagnosis of UA. (See 'Clinical and laboratory features' above and 'Diagnostic evaluation' above.)

Clinical features – Patients determined to have UA typically have the following features:

Symptoms for several weeks to months

Morning stiffness

Less than four swollen joints

Arthritis affecting the upper extremities more often than the lower extremities

Normal or 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 with UA. (See 'Clinical and laboratory features' above.)

Evaluation and differential diagnosis – The diagnostic evaluation includes a medical history, physical examination, and laboratory and imaging studies to confirm the presence of an inflammatory arthritis (ie, synovitis associated with joint swelling) and to exclude other disorders. Such exclusionary findings may include:

Extraarticular features that suggest another diagnosis

Arthrocentesis consistent with an infectious or crystal arthritis

Imaging studies characteristic of specific arthritic disorders

Some features suggestive of an alternate diagnosis are found in the table (table 2). (See 'Diagnostic evaluation' above and 'Differential diagnosis' above and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Differential diagnosis'.)

Initial pharmacotherapy – We use the following approach for the initial treatment of patients presenting with UA (see 'Initial therapy' above):

Methotrexate for most patients – For most patients, we suggest methotrexate (MTX) rather than other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (Grade 2B). We use MTX for most patients because it is widely available, well tolerated, and effective for a broad range of inflammatory arthritides, including rheumatoid arthritis (RA) and UA.

Sulfasalazine for selected patients – Sulfasalazine (SSZ) is appropriate for patients who have predominantly lower-joint disease and lack RF/ACPA (who are more likely to evolve into a spondyloarthropathy) or may become pregnant (since SSZ is safe for both pregnancy and lactation).

Low-dose prednisone for immediate disease control – We also suggest adjunctive therapy with prednisone (Grade 2C). We use only a short course of prednisone for a limited period of time (eg, less than 10 mg daily for less than six months).

Goals of therapy – 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 goals' above.)

Treatment of resistant disease

For patients who fail to respond to a csDMARD other than MTX, we suggest transitioning to MTX (Grade 2C).

For patients who fail to respond to MTX (or who have failed to respond to other csDMARDs and have contraindications to MTX), we suggest adding or transitioning to a tumor necrosis factor (TNF) inhibitor rather than other csDMARDs or other bDMARDs (Grade 2C).

We suggest TNF inhibitors over other agents because of their broad availability and efficacy for a large range of inflammatory arthridities, including RA and spondyloarthritis (SpA). (See 'Resistant to initial therapy' above.)

Antiinflammatory therapies for temporary disease control – We use antiinflammatory therapies, including glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs), for temporary control of disease activity in patients starting/changing DMARD therapy and in patients experiencing a disease flare. (See 'Adjunctive role of antiinflammatory agents' above and 'Drug therapy for flares' above.)

Pretreatment and monitoring strategies – 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 and treatment duration' above.)

Prognosis – The definition of UA varies across studies. However, approximately 10 to 40 percent of patients with UA will remit spontaneously within one year, while 13 to 55 percent will eventually be rediagnosed with RA. Approximately 21 to 87 percent of patients initially diagnosed with UA will not differentiate into another diagnosis, even after one to two years of follow-up. (See 'Prognosis' above.)

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Topic 17052 Version 24.0

References

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