Undifferentiated Inflammatory Arthritis in Adults PDF

7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate Official reprint from UpToDate® www.uptodate.com © 2024 UpToDate, Inc. and/or its a...

7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate Official reprint from UpToDate® www.uptodate.com © 2024 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Undifferentiated inflammatory arthritis in adults AUTHOR: Josef S Smolen, MD SECTION EDITOR: Simon M Helfgott, MD DEPUTY EDITOR: Philip Seo, MD, MHS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2024. This topic last updated: Feb 05, 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".) https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&sel… 1/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate EPIDEMIOLOGY Prevalence – An undifferentiated arthritis (UA) is present in approximately a quarter to a third of patients presenting with 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. 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 : 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 : 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 https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&sel… 2/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate 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) , especially since 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. DIAGNOSTIC EVALUATION Undifferentiated arthritis (UA) is a diagnosis of exclusion. Therefore, most 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 by detecting joint swelling. Joint swelling can generally be identified with a musculoskeletal examination alone. However, imaging can be helpful to confirm equivocal findings on physical examination. Confirm presence of clinical joint swelling — We perform a musculoskeletal examination to confirm the presence of swelling in at least one joint, which is the minimum necessary to be diagnosed with UA. Joint swelling caused by synovitis is characterized by soft tissue swelling along the joint margins. "Warm" joint swelling and redness are primarily related to crystal-induced arthritis, but in RA and undifferentiated arthritis it is usually "cold." There is tenderness to palpation, and a joint effusion may be present. UA cannot be diagnosed in a patient without clinically evident joint swelling, which indicates the presence of synovitis. Joint pain, joint tenderness, and imaging abnormalities (in the absence of 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 https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&sel… 3/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate 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 lower cost and greater 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 clinically evident joint swelling. The specificity of ultrasound or MRI findings for UA in the absence of joint swelling on physical examination is not clear. 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. 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), https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&sel… 4/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate 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. 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. 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. 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 a large joint (eg, knee or shoulder) or the wrist to exclude diagnoses such as infectious arthritis or crystal disease. Testing should include a cell count, white blood cell (WBC) differential, Gram stain, and culture. The synovial fluid should also be examined carefully for evidence of crystals, which https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&sel… 5/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate would be 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 any family history of a disease associated with inflammatory arthritis, such as: Ankylosing spondylitis Systemic rheumatologic disease (eg, SLE) Psoriasis Inflammatory bowel disease Uveitis 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, absence 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 use of laboratory testing 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 https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&sel… 6/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate 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 be indistinguishable 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 approach to treatment of 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 as 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 inflammation and prevent irreversible joint damage [1-6,29-33]. https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&sel… 7/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate 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 that of chronic UA. 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 for evaluation by 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 decision-making shared between 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 such as synovectomy 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 laboratory tests: Complete blood count, blood urea nitrogen, creatinine, and aminotransferases as baseline values for comparison when monitoring 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 https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&sel… 8/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate DMARD (bDMARD), are discussed in the table ( table 3). Our approach to the pretreatment evaluation of patients with UA is similar to that 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. At doses of oral MTX above 15 mg weekly or higher, MTX can be administered in two equal split doses on the same day once weekly to enhance oral absorption. 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. 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). https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&sel… 9/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate 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, especially if they test positive for the human leukocyte antigen B27 (HLA-B27), for which SSZ 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 shown unequivocally to be superior to monotherapy in this population [42,43]. 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 whose clinical presentation resembles that of 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 according to a composite score such as the Clinical Disease Activity Index (CDAI) 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 to treat both RA and psoriatic arthritis (PsA). In patients who have had a partial response to MTX, it would be reasonable to consider adding LEF rather than transitioning to another agent. However, there is an increased risk of transaminitis associated with this approach. Therefore, transitioning to a biologic agent may be associated with fewer complications than using LEF and MTX in combination. (See 'Resistant to initial therapy' below.) https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&s… 10/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate 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 add low-dose prednisone to the treatment of patients with newly diagnosed UA 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 [44-47]. 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 during 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 over 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 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 according to a composite score such as the CDAI 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 [48-51]. (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: https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&s… 11/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate Clinical experience in patients with UA [1-3,52-59] (see 'Rationale for csDMARDs in undifferentiated arthritis' below) Evidence supporting this strategy in patients with RA, consistent with EULAR RA management recommendations (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 : - 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. - Although overall, patients who were treated with DMARDs had higher level of joint damage than patients who were not treated, this likely reflected the greater disease severity at baseline of patients who received immunosuppression. 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 [62,63]. 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. After two years of follow-up, equal numbers of patients in both groups developed RA. However, patients treated with MTX had https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&s… 12/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate 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 that of late disease [64,65]. Also, differences in deoxyribonucleic acid (DNA)-methylation status have been observed in UA patients who progressed to RA. A window of opportunity related to these characteristics may also exist in UA, since UA may represent an early state of RA in a considerable number of patients. Treating during this period could be more effective than if treatment were delayed, increasing the possibility of a biologic DMARD-free remission [67-71]. Risks of untreated disease – The risk of inadequately controlled arthritis also includes systemic effects, such as future cardiovascular disease and osteoporosis, which may be brought about and aggravated by the inflammatory state [30,72,73], particularly in patients who test positive for RF [74,75]. Modest risks of immunosuppression – The risks of MTX (especially with folate supplementation) or SSZ are generally modest, and their adverse effects have become well recognized, with many decades of experience in using of these agents and in monitoring, preventing, and managing their risks. (See "Major adverse 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. Avoiding bDMARDs for initial therapy — We generally avoid starting treatment of UA with bDMARDs because that approach would risk overtreating 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 [77-80]. An additional concern with the use of tumor necrosis factor (TNF) inhibitors is their somewhat increased risk of opportunistic infections and other adverse effects. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Adverse effects'.) https://www.uptodate.com/contents/undifferentiated-inflammatory-arthritis-in-adults/print?search=artritis seronegativa&source=search_result&s… 13/38 7/5/24, 2:40 PM Undifferentiated inflammatory arthritis in adults - UpToDate 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 according to a composite score such as the CDAI 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 treatment, the approach depends on the regimen used for initial therapy: Methotrexate resistant – In patients who have responded inadequately to MTX, we add or transition to monotherapy with a biologic agent. Resistant to a csDMARD other than methotrexate – In patients who have responded inadequately 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 UA with nonsteroidal antiinflammatory drugs (NSAIDs) and/or short-term (