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NICE guidance; RA in adults management 2018

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NICE guidance; RA in adults management 2018

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This guideline covers diagnosing and managing rheumatoid arthritis. It aims to improve quality of life by ensuring that people with rheumatoid arthritis have the right treatment to slow the progression of their condition and control their symptoms. People should also have rapid access to specialist care if their condition suddenly worsens.

NICE has also produced technology appraisal guidance on drug treatment for rheumatoid arthritis.

In October 2020, we amended the 'treat to target' recommendations to clarify that multiple disease-modifying anti-rheumatic drugs can be offered one after the other to achieve treatment targets.

Recommendations

This guideline includes new and updated recommendations on:

It also includes recommendations on:

Who is it for?

Healthcare professionals

Commissioners and providers

People with rheumatoid arthritis and their families and carers

Guideline development process
How we develop NICE guidelines
This guideline updates and replaces NICE guideline CG79 (February 2009).

Your responsibility

The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals and practitioners are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or the people using their service. It is not mandatory to apply the recommendations, and the guideline does not override the responsibility to make decisions appropriate to the circumstances of the individual, in consultation with them and their families and carers or guardian.

All problems (adverse events) related to a medicine or medical device used for treatment or in a procedure should be reported to the Medicines and Healthcare products Regulatory Agency using the Yellow Card Scheme.

Local commissioners and providers of healthcare have a responsibility to enable the guideline to be applied when individual professionals and people using services wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with complying with those duties.

Commissioners and providers have a responsibility to promote an environmentally sustainable health and care system and should assess and reduce the environmental impact of implementing NICE recommendations wherever possible.

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Rheumatoid arthritis in adults: management

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This guideline covers diagnosing and managing rheumatoid arthritis.

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NRAS - National Rheumatoid Arthritis Society

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We use cookies to give you the best possible online experience. If you continue, we'll assume you are happy for your web browser to receive all cookies from our website. See our cookie policy for more information.

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Arthritis Care - Helping You Live Well With Arthritis

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Welcome to Arthritis Care, the UK's largest organisation working with & for people with arthritis. We offer a number of services for people with arthritis.

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Overview of rheumatoid arthritis, a long-term disease that usually affects the joints

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Rheumatoid Arthritis (RA) - Musculoskeletal and Connective Tissue Disorders - Merck Manuals Professional Edition

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Learn about the causes, symptoms, diagnosis & treatment of Joint Disorders from the Professional Version of the Merck Manuals.

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Rheumatoid arthritis (musculoskeletal manifestations) | Radiology Reference Article | Radiopaedia.org

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Rheumatoid arthritis (RA) is a chronic multi-system disease with predominant musculoskeletal manifestations. Being a disease that primarily attacks synovial tissues, RA affects synovial joints, tendons and bursae. Refer to the related articles f...

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rheumatoid arthritis hand imaging overview

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Rheumatoid Arthritis Hand Imaging: Overview, Radiography, Computed Tomography

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Rheumatoid arthritis (RA) is a systemic inflammatory disease that results in cartilage and bone destruction. RA is characterized by a typical pattern and distribution of synovial joint involvement.

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EULAR recommendation for management of RA with synthestic and biological DMARDS

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EULAR recommendation for management of RA with synthestic and biological DMARDS

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ARMA (Arthritis & Musculoskeletal Alliance)

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ARMA (Arthritis & Musculoskeletal Alliance)

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An umbrella body bringing together patients and clinicians to improve MSK health. Includes published standards of care for Inflammatory arthritis (UK) and webinars on lots of relevant topics.

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ARMA welcomes Government roadmap for work and health, but emphasises need for rapid progress

The Arthritis and Musculoskeletal Alliance welcomed the announcement today of Improving Lives: the future of work, health and disability , but emphasises the need for fast progress for people with musculoskeletal conditions. Improving Lives sets out plans to transform employment prospects for disabled people and those with long term health conditions over the next 10 years.

Conditions of the bones, joints muscles - musculoskeletal conditions - are the leading cause of people's inability to work and disability in the UK. Less than two-thirds of working age people with a musculoskeletal condition are in work.

Sue Brown, chief executive of ARMA said, "I very much welcome the Government's firm recognition of the need to address musculoskeletal conditions and work. We look forward to working closely with Government to ensure the details are right, but it's vital that there is rapid progress if we are to curb the growing impact of musculoskeletal conditions on people's working lives.

"The specific proposals in the document for a Challenge Fund need to ensure that musculoskeletal conditions are a high priority in their activity."

Watch recordings of past webinars from the MSK series.

Self-care workforce skills

Joint Pain Advisor Webinar

Getting It Right First Time Masterclass

Clinical Networks: Transforming MSK Care

Physiotherapy in Primary Care

The Musculoskeletal Health Questionnaire

New models of MSK Masterclass

Work & Health MSK Webinar

The MSK Webinar Series
Recent event:

Sport, Exercise and Musculoskeletal Training and Delivery in the NHS
Webinar recording available now
The Faculty of Sport, Exercise and Musculoskeletal Medicine presents
the scope of work of a Sport & Exercise (SEM) Consultant, and an example of how to set up and run a successful NHS Musculoskeletal (MSK) service.

Visit the webinar page.

Public Health England's Active 10

Over 6.3 million adults aged 40 to 60 do not achieve 10 minutes of continuous brisk walking over the course of a month and are missing out on important health benefits. The new One You physical activity campaign is encouraging adults to build 10 minutes continuous brisk walking into their day as a simple way to improve their health, which could save the NHS over £0.9 billion per year.

Read the evidence reviewed by Public Health England and learn about the Active 10 app.

ARMA's Policy Positions

ARMA published two policy position papers in 2016:

Like previous documents, these are the result of input from across our membership and our community, and contain recommendations for policy makers.

Please share widely.

Policy Position Paper on Prevention
of Musculoskeletal Conditions

ARMA highlights a need for transformation so that Care and Public Health systems go beyond merely tackling musculoskeletal conditions when they arise, to promoting good, lifelong musculoskeletal health.

Click here to access the document.

Policy Position Paper on Joint Replacement Surgery

The Arthritis and Musculoskeletal Alliance is extremely concerned about increasing restrictions to access NHS services for joint replacements and the impact on people with musculoskeletal conditions.

Click here to access the document.

Musculoskeletal toolkit launched to help employers support people with musculoskeletal conditions

ARMA worked with Public Health England and Business in the Community to develop a new toolkit for employers in the workplace, which launched at the Health and Wellbeing at Work Conference in the NEC today (7 March 2017). Musculoskeletal conditions are an important consideration for businesses as they are a leading cause of pain and disability in the UK, affecting many employees.

The toolkit draws together information for employers to support staff in the prevention, early identification, management and adaptation for people affected by musculoskeletal conditions. The musculoskeletal toolkit is a simple step-by-step guide dealing with back, neck, muscle and joint pain at work. It will help employers access the best free resources that are available for their organisation and employees.

You can access the toolkit from the Business in the Community website.

World Health Organisation landmark action plan will tackle tidal wave of musculoskeletal conditions

The Arthritis and Musculoskeletal Alliance, an alliance of prominent health charities, professional and research bodies, today [Thursday 15th September 2016] welcomed a ground-breaking World Health Organisation action plan to tackle musculoskeletal conditions in Europe.

The Action Plan was also welcomed internationally by the Global Alliance for Musculoskeletal Health, calling on the European Region to implement the Action Plan and all countries of the world to adopt a similar approach to tackling musculoskeletal conditions.
Sign up to the Global Alliance's e-petition.
Response to Improving Lives: The Work, Health and Disability Green Paper

UK Government consultation

ARMA welcomes the recognition in the Improving Lives: The Work, Health and Disability Paper of the need to address musculoskeletal conditions and work.

Musculoskeletal conditions are among the commonest causes of people's inability to work and, as evidenced in the Global Burden of Disease study (2015), are the single biggest cause of pain and disability in the UK. Less than two-thirds of working age people with musculoskeletal conditions are in work. MSK conditions are the leading cause of sickness absence, resulting in 30.6 million working days lost each year and one in five visits to the GP. They are associated with anxiety and depression. The impact of MSK problems on work is predicted to increase and with people working into older ages, the impact on work will also increase.

We look forward to working with the Joint Work and Health Unit and ARMA members to provide more detailed support from the musculoskeletal community to realise the opportunities that the Green Paper proposes.

Read the full response.

New ARMA Leaflet

ARMA has released an A5 leaflet to support its activity, promoting good musculoskeletal health.

The leaflet features key messages on what is needed to provide the right care for musculoskeletal conditions,
in the right place, at the right time.

ARMA is the alliance providing a collective voice for the arthritis and musculoskeletal community in the UK.
Together, ARMA and its member organisations work to improve quality of life for all those living with musculoskeletal (MSK) disorders in the UK.

We aim to foster co-operation between charities and professional organisations, working to enhance understanding and mutual support between individuals and organisational bodies.

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ARMA - Arthritis and Musculoskeletal Alliance

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The Arthritis and Musculoskeletal Alliance welcomed the announcement today of Improving Lives: the future of work, health and disability , but emphasises the need for fast progress for people with musculoskeletal conditions. Improving Lives sets out plans to transform employment prospects for disabled people and those with long term health conditions over the next 10 years.

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Rheumatoid arthritis (RA) is a chronic inflammatory immune mediated disorder where synovial proliferation, pannus formation and bone erosions are histological hallmarks [ 1]. Proinflammatory cytokines play a major role in development of disease and clinical progression. Anti-cytokine therapy has brought a major impact in RA management [ 2].

Clinical assessment of RA patients includes history, physical examination, scores of disease activity and questionnaires addressing quality of life. As far as imaging is concerned, conventional radiograms and magnetic resonance imaging (MRI) are well-recognized support methods for clinical assessment and response to therapy. They have intrinsic problems, nevertheless. Radiograms cannot evaluate joint inflammation and show low sensitivity for damage; MRI, although sensitive, is expensive and not widely available [ 1, 2].

In recent years, high-resolution musculoskeletal ultrasound (MSUS) has been increasingly used in rheumatological practice worldwide [ 3]. While MSUS gray-scale (GS) usually identifies synovial proliferation, power Doppler (pD) may recognize active inflammation and neoangiogenesis. Both parameters seem worthy of utilization in the follow-up of RA patients [ 4]. In addition, MSUS is also reliable for the detection of bone erosions [ 5] as well as for the detection of subclinical synovitis and prediction of disease relapse and structural progression [ 6].

Although unequivocally useful in RA, MSUS has intrinsic reproducibility issues that may be optimized through standardized training and recommendations. In 2010, a multinational group of 25 Rheumatologists from the American Continent participated in a consensus-based questionnaire and established the first recommendations and guidelines for MSUS course training in the Americas [ 7]. Besides, EULAR consensual advice for use of imaging techniques (MSUS included) in the management of RA has been recently proposed [ 8].

In this paper, we review the correlation of MSUS findings with synovial tissue inflammation in RA patients and its implications for a better clinical utilization of this imaging technique. Also, we discuss MSUS clinical application as compared to classical activity parameters. Lastly, we update MSUS techniques and interobserver reliability in RA.

Ultrassound parameters and synovial tissue

Comparison of MSUS findings with features of synovial tissue allows characterizing how far this technique can capture the inflammatory activity that is actually ongoing inside joints.

Andersen et al. studied the correlation between histological synovitis and GS and pD in RA patients and found fairly good correlations between pD and histological features of inflammation and proliferation, namely synovium expression of CD3, CD68, Ki67 and von Willebrand factor (r between 0,44 and 0,57). There were areas of histological inflammation where no pD could be identified [ 9]. Other authors showed that 5 RA patients in DAS remission who had GS but negative pD had low likelihood of relapse after TNF inhibitor tapering and histologically had low infiltrates of macrophages (CD68+), T (CD3+) a B (CD20+) cells [ 10].

In a study of 14 RA patients in remission who were submitted to surgery, 15 synovial samples were collected. GS changes were found in 80% patients, pD detected in 60% of the individuals and MRI synovitis in 86%. Histologically, 4 samples had severe inflammation, 6 moderate, 3 mild and 2 minimal [ 11].

Contrast-enhanced Doppler ultrasound may be superior to pD in translating a dynamic process such as synovitis in RA, in which perfusion may be determinant, but little is known about the correlation of these findings with histological features in the synovium RA. This method has proved to be superior to pD in defining active synovitis, using arthroscopy, but not MRI, as the gold standard [ 21, 22, 23, 24].

Worthy of note, synovial production of IL-6 was found to associate with synovitis as detected by MRI and pD [ 25]. This in accordance with our own results, depicting that IL-6, but not other cytokines, correlated positively with DAS28, swollen joint count, 10-joint pD score and GS/pD of both wrists. In multiple linear regression, the association of IL-6 with 10-joint pD score was maintained even after adjustment for DAS28. There was no correlation of IL-6 with tender joint count, 10-joint GS score, or bone erosion [ 26].

Interestingly, Ball et al. described association of serum IL-6 with arthritis on physical examination and pD score in patients with systemic lupus erythematosus [ 27]. Overall, these findings [ 26, 27] may result from a prominent synovial production of IL-6. In fact, IL-6 stimulates angiogenesis [ 28], and this could eventually explain the association of IL-6 concentrations with a positive pD in RA. A recent report accounted for association of serum IL-6 with MSUS parameters of synovitis in patients with early RA; of importance, serial measurements of IL-6 were linked to structural damage [ 29].

In patients with established RA, a correlation of serum IL-17 with synovial hypertrophy and pD in hand MSUS was documented [ 30]. Interestingly, the presence of Th-17 lymphocytes in synovial tissue was associated with a persistent pD signal, according to a 2010 study [ 31].

As seen, the study of the relationship of MSUS parameters with synovial tissue features is clearly a field open to research, which may add new pathogenic information and help to clarify MSUS usefulness in RA management.

Correlation of MSUS with physical examination, inflammatory markers and patient reported outcomes

For many years, Rheumatologists have been using the disease activity score of 28 joints (DAS28) and other composite scores as gold standard for assessment of RA activity; these tools have clearly brought great progress in treatment monitoring. Even though they are the most extensively validated methods for measuring disease activity to date [ 32], the precise way of objectively defining inflammation is still lacking. MSUS can be worthwhile in this context, since it is more sensitive than physical examination for detection of arthritis according to a number of studies [ 33, 34, 35, 36, 37].

In patients with joint inflammatory symptoms lasting less than 12 months, MSUS significantly increased the classification of patients as RA (31% pretest, 61% post-test) [ 38]. In individuals with established RA, synovial hypertrophy and pD scores of wrists and MCP correlated significantly with physician-recorded clinical outcomes and helped the rheumatologist in clinical decision [ 39].

Of great importance, preliminary data indicated that the MSUS methodology improved the accuracy of the 2010 ACR/EULAR criteria for identifying patients needing methotrexate treatment. GS ≥ 2 and pD ≥ 1 were good indicators of synovitis [ 40].

We have previously reported that pD, GS and bone erosion on MSUS were associated with swollen joint count, but not with joint tenderness [ 47]. Concordance of physical examinationand MSUS assessment seems poor (not more than 50% between the most affected joint and pD signal), and RA structural progression has been more associated with swollen joint count than with pain [ 48, 49, 50].

Correlations studies of MSUS with disease activity are a matter of debate. In a study employing pD score of 22 joints and GS score of 28 joints, a defined correlation of MSUS parameters with classical measures of RA activity (acute phase proteins, DAS28) was found. Differently, correlation of MSUS scores with health assessment questionnaires were weak to moderate [ 51].

In a 2014 study, concordance level of standard activity measures with MSUS was evaluated. For such, a pD score of hands, radiocarpal and MTP joints was utilized. Discrepancies between pD and DAS28 occurred in 29% of cases, promoting changes in therapeutic decision, in other words, supporting DMARD escalation in patients with continuing subclinical synovitis and preventing escalation in symptomatic patients without ultrasonographic synovitis [ 52]. Likewise, Gartner et al. demonstrated pD signal in up to 20% of patients in remission according to DAS28 [ 53].

Recently, it has been shown that the 7-joint GS/pD Backhaus score showed performance comparable to clinical and laboratory data in RA patients under various therapies. Higher score predicted bone erosions after one year. Of interest, Backhaus method was sensitive enough to demonstrate decline in bone erosions in patients who switched biological agents [ 54]. In patients in remission, a link of GS/pD positivity with risk of clinical flare and structural progression was demonstrated by metanalysis in 2014 [ 55].

In an observational study of 307 RA patients, Zufferey et al. demonstrated that many subjects in clinical remission according to classical parameters (DAS28 and ACR/EULAR criteria) showed residual synovitis on GS and pD scan [ 62]. Yoshimi et al. documented synovitis by pD in patients in clinical inactivity and suggested that the pD parameter is essential to confirm "true remission" of RA [ 63].

Recently, a group of authors originally approached the correlation of MSUS with clinical scores in RA patients with and without fibromyalgia. While GS scores correlated with classical parameters in both groups, the pD analysis was more precise by correlating with clinical scores only in patients without fibromyalgia [ 64].

In 68 RA patients evaluated with a six-joint pD method (two MCP, wrists, knees), the global MSUS score correlated moderately with the DAS28; in this survey, pD positivity was a sensitive-to-change method for monitoring the short-term response to anti-TNF agents [ 65]. In a cross-sectional study of 97 RA patients, an inactive disease status defined by a 12-joint pD score (but not clinical parameters) associated, interestingly, with decrease in complement levels in patients treated with biologics [ 66].

In 2015, the ARTIC trial addressed the question if MSUS could correlate with DAS28 defined RA remission criteria. In 238 patients with early RA randomized to perform or not GS/pD MSUS in addition to DAS28, both strategies (MSUS included or not) were effective to estimate remission after two years of therapy [ 67].

In summary, there has been plenty of recent literature looking at the role of MSUS either as a complement to physical examination or as a measure of disease activity. It seems the discrepancies between US findings and clinical findings on articular examination are more important in long standing RA and/or fibromyalgia associated RA patients, where metrics are less reliable (due to difficulties in physical examinations and on pain exacerbation). It remains an open question if MSUS would work as additional or preferential criteria for assessing RA activity. MSUS looks a promising instrument for monitoring RA disease activity, but a greater body of evidence still is required.

Intra and interobserver agreement

Another critical aspect when using MSUS in the evaluation of RA is reproductibility. Inter-reader analysis of the clinical assessment of joint inflammation can itself show some discrepancy [ 68, 69]. Intra and interobserver discrepancies in both acquisition of image and image interpretation have been a matter of concern.

Subclinical joint changes in asymptomatic feet of RA patients were recently assessed. Concordance between MSUS and radiograms was low (kappa 0.08-0.40). Inter-reader agreement was excellent for bone erosion (kappa = 1), good for quantitative synovitis (0.64) and moderate (0.47) for pD signal [ 73].In 2011, the interobserver reliability of a synovitis MSUS resulted in moderate concordance (kappa 0.50) for quantification of synovitis in the radiocarpal joint [ 74].

Szkudlarek et al showed in thirty RA patients with active disease that MSUS agreement was good for erosions (kappa 0.78) and pD (0.72), and excellent for synovitis (0.81) evaluatingfive joints (second and third MCP, second PIP, first and second MTP) that were scanned by two experienced sonographers. [ 75]

The Swiss Sonography in Arthritis and Rheumatism (SONAR) group had previously developed a consistent MSUS method for assessing RA activity utilizing B-mode and pD scores [ 76]. The same group evaluated synovitis and erosion in six differentMSUS machines. Overall, agreement was not more than moderate. Considering only high-quality machines, kappa concordance was better for synovitis (0.64) than erosion (0.41) [ 77].

Yet in 2005, the EULAR promoted the "Train the trainers" course aiming to evaluate MSUS interobserver reliability in RA. Clinically dominant joint regions (shoulder, knee, ankle/toe, wrist/finger) were examined. Concordance was particularly high for bone lesions, bursitis, and tendon tears (kappa = 1). As a whole, interobserver concordance, sensitivities, and specificities were comparable with MRI [ 78].

The reliability of the Backhaus 7-joint score was evaluated in 2012 and the best interobserver concordance was obtained for bone erosions in second MTP (plantar side), with kappa of 1. Agreement for pD in palmar side of wrist was good (0.79). Intraobserver reliability of the method was moderate to substantial [ 79].

In our own experience, we have been employing a 10-joint score exclusively of hand/wrist joints (dorsal aspects of wrists and second and third MCP, and volar aspect of second and third PIP joints of both hands). After evaluating 1380 joints of 60 RA patients, kappa agreement for synovitis ranged from fair to good (0.30-0.70); for cartilage changes, also from fair to good (0.28-0.63; for pD signal, from moderate to absolute agreement (0.53-1); and for erosions, from good to excellent (0.70-0.97) [ 80].

In 2014, the LUMINA European study assessed the reliability of grading MSUS videoclips with hand pathology in RA by employing non-sophisticated internet tools. Intra-reader concordance for GS/pD synovitis was moderate to good (0.52/0.62), while the interobserver agreement for global synovitis (synovitis and tenosynovitis) was not more than moderate (0.45) [ 81].

Also recently, a short collegiate consensus attempted to improve MSUS interobserver reliability. Concordance was good for B mode synovitis (0.75) and excellent for pD (0.88). Kappa values were excelllent for small hand joints, but poor to fair in wrists, elbows, ankles and MTP. Admittedly, the consensus meeting was useful to improve agreement in synovits scores of still images. Moreover, the consensus strongly emphasized the need for standards of image acquisition and interpretation [ 82].

The several studies [ 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82] evaluating reliability of MSUS scores have revealed some variation. As a whole, MSUS seems very reliable for bone erosions (kappa ranging from good to excellent); in turn, the grade of agreement for synovitis, although generally moderate to good, has shown more fluctuation. Standardized training seems essential to improve all these outcomes.

Ultrasound scores

A high-resolution machine with a linear high-frequency probe (7.5-18 MHz) should be utilized for evaluation of small joints. In the most widely used scoring systems, semiquantitative GS, generated in the B-mode, synovial proliferation is classified as: zero (absent); 1) mild (slight hipoechoic or anechoic image in articular capsule); 2) moderate (presence of elevation of articular capsule); 3) severe or marked (important distension of articular capsule). The semiquantitative scale of pD signal stratifies inflammatory activity and angiogenesis as follows: zero (absent); 1) mild (one pD signal); 2) moderate (two or more pD signal, meaning < 50% of intraarticular flow); 3) severe or marked (> 50% of intraarticular flow) [ 83]. In addition, Carotti et al. reported that the resistive index (RI), using spectral Doppler, quantified inflammation in microvessels of finger joints and wrists and discriminated RA synovitis (higher values) from normal subjects [ 84]. Bone erosions, in turn, are defined according to the OMERACT criteria and are classified as present or absent [ 85]. Figure 1 illustrates MSUS findings in normal and RA hand joints.

Imagens of a normal MCP joint and an abnormal MCP joint of a RA patient. a Normal musculoskeletal ultrasound (MSUS) of third metacarpophalangeal (MCP) joint, longitudinal dorsal aspect; b Synovial proliferation grade 3 on second MCP, longitudinal dorsal aspect (arrow in hypoechoic area); c Synovial proliferation (arrow) and power Doppler (pD) captation grade 2 on second MCP, longitudinal dorsal aspect; d Interruption of cortical bone (erosion) on second MCP, radial aspect, longitudinal scan (plus sign); e MSUS of a patient with long-standing rheumatoid arthritis. Findings of second MCP (longitudinal dorsal aspect) include synovial proliferation grade 3 (arrow), pDcaptation grade 2 and bone erosion (plus sign)

There has been no agreement regarding which joints and tendons should be systematically examined in MSUS of RA patients. A number of different methods and scores have been advocated, without wide concordance to date. As a whole, it was proposed to include dorsal and volar exam of the hands in daily practice and clinical trials [ 33], but volar examination might not be consensual.

Historically, MSUS scores were firstly proposed in 2005 by two groups of authors [ 83, 86]. Scheel et al. described different MCP and PIP scores for GS and pD [ 86]. In 2006, Loeuille et al. reported a 7-joint GS/pD score including wrist, MCP and MTP of dominant side [ 87]. One year later, an 8-joint system evaluating GS/pD of MCP and MTP of dominant side was proposed by Hensch et al. [ 88]. In 2008, Iagnocco et al. designed a 10-joint method including MCP, PIP, wrist and knee including tenosynovitis, bursitis and erosion in addition to GS/pD [ 89]. Also in 2008, a 12-joint simplified MSUS including elbow, wrist, MCP, knee and ankle was reported by Naredo [ 90].

The 7-joint MSUS score proposed by Backaus et al. in 2009 has been the most largely utilized in recent literature and includes five hand and two foot joints of the clinically dominant side: wrist, second and third MCP and proximal interphalangeal (PIP), and second and fifth metatarsophalangeal (MTP) joints. This score also evaluated tenosynovitis and erosive changes [ 91].

In 2010, Hammer et al. proposed a 78-joint GS/pD score [ 92]. In 2012, a 6-joint MSUS score of wrists, MCP and knees utilized synovial effusion in conjunction with the synovial proliferation and pD parameters. This score was practical, trustworthy and sensitive-to-change for evaluating synovial inflammation in RA [ 93].

Also very recently, a 12-joint score evaluating synovial hypertrophy by B-mode technology and synovitis by pD signal was described. The wrist-hand-ankle-MTP assessments were able to predict unstable remission in RA patients presumably inactive on methotrexate therapy [ 97].

With such heterogeneity in the previously mentioned scores, it is important to verify if scores with low number of joints correlate well with scores involving more joints, in order to find a set feasible for clinical daily practice. For instance, the 7-joint Backaus score significantly correlated with a 12-joint instrument for monitoring of response to infliximab in RA patients, according to a 2016 study [ 98].

A novel GS/pD score composed of a bilateral approach of six hand joints (first, second and third MCP joints, second and third PIP joints and radiocarpal joint), two feet joints (second and third MTP) and, in addition, one tendon (extensor carpi ulnaris), performed better than previous scores in a longitudinal analysis [ 99]. Using a data-driven approach, the same group of authors set out to validate a new MSUS score in a large survey of early or established RA. The set comprising GS/pD scores of seven joints/two tendons (first and second MCP, second MCP, third PIP, radiocarpal, elbow, first and second MTP, tibialis posterior tendon, extensor carpi ulnaris tendon) preserved most of the information when compared to a 9-joint score (which added fifth MCP and fifth MTP) [ 100].

A systematic review of 14 studies published in 2011 did not yield a consensus as to the minimal number of joints to be included in a global MSUS score [ 101]. Newer recommendations after critical analysis of the most recent MSUS scores are expected. Table 1 lists, in chronological order, the MSUS scores described so far.

Table 1 Musculoskeletal ultrasound scores described in chronological order

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Ultrasound and its clinical use in rheumatoid arthritis: where do we stand?

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High-resolution musculoskeletal ultrasound (MSUS) has been increasingly employed in daily rheumatological practice and in clinical research. In rheumatoid arthritis (RA), MSUS can be now considered a complement to physical examination. This method evaluates synovitis through gray-scale and power Doppler and it is also able to identify bone erosions.

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INTRODUCTION - Rheumatoid arthritis (RA) is a symmetric, inflammatory, peripheral polyarthritis of unknown etiology. It typically leads to deformity through the stretching of tendons and ligaments and destruction of joints through the erosion of cartilage and bone. If it is untreated or unresponsive to therapy, inflammation and joint destruction lead to loss of physical function, inability to carry out daily tasks of living, and difficulties in maintaining employment.

Early recognition and treatment with disease-modifying antirheumatic drugs (DMARDs) is important in achieving control of disease and prevention of joint injury and disability. However, in patients with early disease, the joint manifestations are often difficult to distinguish from other forms of inflammatory polyarthritis. The more distinctive signs of RA, such as joint erosions, rheumatoid nodules, and other extraarticular manifestations, are seen primarily in patients with longstanding, poorly controlled disease but are frequently absent on initial presentation.

This topic will review the approach to the diagnosis and differential diagnosis of RA. The clinical features of this disorder, its extraarticular manifestations, and laboratory markers that are clinically useful in the diagnosis of RA are discussed in detail separately. (See "Clinical manifestations of rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis" and "Biologic markers in the diagnosis and assessment of rheumatoid arthritis".)

We focus especially on the following for the purposes of diagnosis:

●We perform a thorough medical history, with particular attention to joint pain, reported swelling, and the presence, location (peripheral joints rather than low back), and duration (at least 30 minutes) of morning stiffness. The absence of other conditions or symptoms suggesting an alternative diagnosis, such as psoriasis, inflammatory bowel disease (IBD), or a systemic rheumatic disease such as systemic lupus erythematosus (SLE), helps to exclude other disorders.

Symptoms of arthritis that have been present for a short time (for example, less than six weeks) may well be due to an acute viral polyarthritis rather than to RA. The longer symptoms persist, the more likely the diagnosis of RA becomes. Thus, in patients presenting very early, close observation with frequent follow-up appointments is required, with repeated serologic analysis for anti-cyclic citrullinated peptide (CCP) antibodies, rheumatoid factor (RF), and acute phase reactants. In a minority of patients, several such visits are required before the differential diagnosis between RA and viral arthritis becomes established. (See "Clinical manifestations of rheumatoid arthritis", section on 'Typical 'classic' RA' and 'Differential diagnosis' below.)

●A complete physical examination is indicated to assess for synovitis, including the presence and distribution of swollen or tender joints and limited joint motion; extraarticular disease manifestations, such as rheumatoid nodules; and signs of diseases, such as SLE or psoriasis, included in the differential diagnosis. (See "Clinical manifestations of rheumatoid arthritis", section on 'Symptoms and physical findings' and "Rheumatoid nodules" and 'Differential diagnosis' below.)

●We perform the following laboratory tests, which support the diagnosis if positive and/or elevated:

●We perform the following testing in all patients, which may be helpful in the differential diagnosis of RA and as baseline testing for monitoring of disease activity or progression and medication safety:

*Antinuclear antibody (ANA) testing - A negative ANA helps exclude SLE and other systemic rheumatic diseases; the ANA may be positive in up to one-third of patients with RA. In patients with a positive ANA, anti-double stranded DNA and anti-Smith antibody testing should also be performed; these antibodies have high specificity for SLE. (See "Measurement and clinical significance of antinuclear antibodies".)

*Complete blood count (CBC) with differential and platelet count, tests of liver and kidney function, serum uric acid, and a urinalysis - The CBC is often abnormal in RA, with anemia and thrombocytosis consistent with chronic inflammation. Liver and kidney testing abnormalities indicate a disorder other than RA; if caused by comorbid conditions, they may affect therapeutic choices or drug dosing. Hyperuricemia may prompt additional efforts, including arthrocentesis and crystal search, to exclude gout; polyarticular gout can infrequently be mistaken for RA. (See "Hematologic manifestations of rheumatoid arthritis", section on 'Anemia of chronic disease' and "Hematologic manifestations of rheumatoid arthritis", section on 'Platelet abnormalities' and 'Differential diagnosis' below.)

*Radiographs of the hands, wrists, and feet - We obtain radiographs during the initial evaluation primarily as a baseline for monitoring disease progression. However, characteristic joint erosions may be observed in patients presenting with symptoms for the first time and, hence, aid in diagnosis. Additionally, in patients with other disorders, such as psoriatic arthritis, spondyloarthropathy, gout, or chondrocalcinosis, radiographic changes more characteristic of these conditions may point to an alternative diagnosis. (See '2010 ACR/EULAR criteria' below and 'Differential diagnosis' below and "Clinical manifestations of rheumatoid arthritis", section on 'Imaging'.)

●We perform the following studies in selected patients:

*Serologic studies for infection - In patients with a very short history (for example, less than six weeks) particularly those who are seronegative for anti-CCP and RF, we perform serologic testing for human parvovirus B19, hepatitis B virus (HBV), and hepatitis C virus (HCV). In areas endemic for Lyme disease, we perform serologic studies for Borrelia as well. In people who live in or have traveled to parts of the world where mosquito ( Aedes aegypti and Aedes albopictus)-bite transmitted viral diseases are prevalent, chikungunya virus infection should be suspected in patients with fever and arthralgia, as this may be followed by a chronic polyarthritis; diagnosis is confirmed by serologic tests. (See 'Viral polyarthritis' below and "Viruses that cause arthritis" and "Diagnosis of Lyme disease" and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)

*Magnetic resonance imaging (MRI) and ultrasound - MRI studies and ultrasonography do not have an established role in the routine evaluation of patients with polyarthritis. However, MRI and ultrasound are more sensitive than radiography at detecting changes resulting from synovitis and may be helpful in establishing the presence of synovitis in patients with normal radiographs and uncertainty regarding either the diagnosis or the presence of inflammatory changes, such as patients with obesity or subtle findings on examination. (See "Clinical manifestations of rheumatoid arthritis", section on 'Imaging'.)

Our diagnostic criteria - The diagnosis of rheumatoid arthritis (RA) can be made when the following clinical features are all present:

●Inflammatory arthritis involving three or more joints. (See "Clinical manifestations of rheumatoid arthritis", section on 'Symptoms and physical findings'.)

●Positive rheumatoid factor (RF) and/or anti-citrullinated peptide/protein antibody (such as anti-cyclic citrullinated peptide [CCP])) testing. (See "Biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.)

●Elevated levels of C-reactive protein (CRP) or the erythrocyte sedimentation rate (ESR). (See "Biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Erythrocyte sedimentation rate'.)

●Diseases with similar clinical features have been excluded, particularly psoriatic arthritis, acute viral polyarthritis, polyarticular gout or calcium pyrophosphate deposition disease, and systemic lupus erythematosus (SLE). (See 'Differential diagnosis' below.)

●The duration of symptoms is more than six weeks.

These criteria are consistent with the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA. (See '2010 ACR/EULAR criteria' below.)

The diagnosis of RA may also be made in some patients who do not meet all of our criteria. (See 'Patients not meeting above criteria' below.)

Inflammatory arthritis - Arthritis is typically present in the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the hands. The wrists are also commonly involved, as are the metatarsophalangeal (MTP) joints in the feet, but any upper or lower extremity joint may be affected. Symmetric polyarthritis, particularly of the MCP, MTP, and/or PIP joints, strongly suggests RA. Although distal interphalangeal (DIP) joint disease can occur in patients with RA, DIP involvement strongly suggests a diagnosis of osteoarthritis or psoriatic arthritis. (See "Clinical manifestations of rheumatoid arthritis", section on 'Symptoms and physical findings' and 'Osteoarthritis' below and 'Psoriatic arthritis' below.)

Antibodies to citrullinated peptides/proteins are usually measured by enzyme-linked immunosorbent assays (ELISAs) using CCPs as antigen. Anti-CCP antibodies have a similar sensitivity to RF for RA but have a much higher specificity (95 to 98 percent) [ 1-4]. The specificity is greater in patients with higher titers of anti-CCP antibodies (at least three times the upper limit of normal). Another test, anti-mutated citrullinated vimentin, gives similar results to anti-CCP and is used as an alternative in some laboratories [ 5]. (See "Biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.)

Acute phase reactants - Elevations of the ESR and/or CRP level are consistent with the presence of an inflammatory state, such as RA. Normal acute phase reactants may occur in untreated patients with RA, but such findings are very infrequent. The degree of elevation of these acute phase reactants varies with the severity of inflammation. As an example, an ESR of 50 to 80 is not uncommon in patients with severely active RA. By comparison, an ESR of 20 to 30 can be observed with only a few mildly to moderately active joints. Although increased levels of acute phase reactants are not specific for RA, they are often useful for distinguishing inflammatory conditions from noninflammatory disorders that present with musculoskeletal symptoms (eg, osteoarthritis or fibromyalgia). (See "Acute phase reactants" and "Biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Erythrocyte sedimentation rate' and "Biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'C-reactive protein'.)

Patients not meeting above criteria - The diagnosis of RA may also be made in patients without all the criteria described in the previous section. Examples include the following:

● Seronegative RA - Patients who lack both RF and anti-CCP antibodies may be diagnosed with RA based upon findings otherwise characteristic of RA if appropriate exclusions have been met. Such patients with seronegative RA differ from anti-CCP-positive patients genetically and in their environmental risks, disease severity, and clinical responsiveness to some medications [ 6]. Additional research is needed to better characterize this population. (See "Biologic markers in the diagnosis and assessment of rheumatoid arthritis".)

● Recent onset RA -Patients with disease for less than six weeks may be diagnosed with RA based upon findings otherwise characteristic of RA, including anti-CCP antibodies, if testing for viral serologies is negative and if other appropriate exclusions have been met. (See 'Evaluation for suspected RA' above and 'Viral polyarthritis' below.)

● Inactive RA - Patients without active arthritis or elevated acute phase reactants (eg, due to treatment of recent onset disease or with longstanding disease) may be diagnosed with RA based upon well-documented past findings characteristic of RA, especially in the presence of positive testing for RF and anti-CCP, or typical bone erosions on radiography, and in the absence of an alternative more likely diagnosis.

Patients in the several categories above, and other patients who should be diagnosed with RA but do not meet our standard criteria, will generally have findings that are consistent with the 2010 ACR/EULAR classification criteria for RA [ 7,8]. These criteria were developed for the classification of patients with RA for the purpose of epidemiologic studies and clinical trials, not primarily for clinical diagnosis. Nevertheless, the same features that are of value in classification tend to be useful for the purpose of diagnosis in clinical practice. Further study is required to establish their utility as diagnostic criteria in general practice. (See 'Classification criteria' below.)

●Number and site of involved joints

*2 to 10 large joints (from among shoulders, elbows, hips, knees, and ankles) = 1 point

*1 to 3 small joints (from among the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists) = 2 points

*4 to 10 small joints = 3 points

*Greater than 10 joints (including at least 1 small joint) = 5 points

●Serological abnormality (rheumatoid factor or anti-citrullinated peptide/protein antibody)

*Low positive (above the upper limit of normal [ULN]) = 2 points

*High positive (greater than three times the ULN) = 3 points

●Elevated acute phase response (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]) above the ULN = 1 point

●Symptom duration at least six weeks = 1 point

In addition to those with the criteria above, which are best suited to patients with newly presenting disease, the following patients are classified as having RA:

●Patients with erosive disease typical of RA with a history compatible with prior fulfillment of the criteria above

●Patients with longstanding disease, including those whose disease is inactive (with or without treatment) who have previously fulfilled the criteria above based upon retrospectively available data

Thus, while these criteria were very good at separating inflammatory from noninflammatory arthritis, the major drawback of the 1987 criteria has been their insensitivity in identifying some patients with early disease who subsequently develop typical established RA [ 10]. On the other hand, the criteria did not require any exclusions, and patients could initially fulfill the diagnostic criteria but occasionally evolve into other diagnoses, particularly systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, mixed connective tissue disease, psoriatic arthritis, and crystalline arthritis.

Viral polyarthritis - A number of viral infections may cause an acute viral polyarthritis.

Serologic testing can help identify patients with HBV, HCV, or human parvovirus B19 in some individuals with early disease, but a viral etiology cannot always be excluded until after symptoms are present for at least six to eight weeks in the absence of diagnostic serologic testing for a specific virus (see "Viruses that cause arthritis") Unlike rheumatoid factor (RF) (which may occur in patients with a variety of infections, including HCV infection), anti-cyclic citrullinated peptide (CCP) antibodies are usually negative in patients with HCV infection who do not have RA. (See "Biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.)

One such alphavirus, Chikungunya, has become a global disease with increasing world travel and has caused large outbreaks in Italy, India, Indian Ocean islands, and in the Caribbean region and surrounding countries [ 16,17]. Patients with more persistent disease can mimic seronegative RA clinically to a sufficient degree to satisfy the 2010 classification criteria for RA if the initial symptoms of fever and rash and history of travel to an endemic region are not appreciated [ 18]. Serologic studies can help to document exposure to the Chikungunya virus. (See "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

Alphavirus infections generally resolve over three to six months. The diagnosis of alphavirus infection can be made by appropriate serologic testing in travelers from endemic areas with persistent arthritic symptoms. (See "Viruses that cause arthritis", section on 'Alphaviruses' and "Chikungunya fever: Epidemiology, clinical manifestations, and diagnosis".)

●A large joint arthritis has been reported in association with human T lymphotropic virus type 1 (HTLV-I) [ 19]. These infections are sometimes associated with the presence of RFs (usually in low titer), antinuclear antibodies (ANA), and elevated acute phase reactants. HTLV-I infections can generally be distinguished from RA by the finding of specific antiviral antibodies and the typically self-limited nature of arthritis associated with HTLV-I.

Other systemic rheumatic diseases - Early RA may be difficult to distinguish from the arthritis of systemic lupus erythematosus (SLE), Sjögren's syndrome, dermatomyositis (DM), or overlap syndromes such as mixed connective tissue disease. In contrast with RA, these disorders are generally characterized by the presence of other systemic features, such as rashes, dry mouth and dry eyes, myositis, or nephritis, and by various autoantibodies not seen in RA. Additionally, the relative responses of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be less well-correlated with each other in other diseases, particularly SLE, than in RA. Whereas both are commonly raised in RA, the CRP is often normal or only minimally elevated in patients with active SLE even when the ESR is elevated.

Taken together, the pattern of longstanding disease, morning stiffness, symmetric arthritis, subcutaneous nodules, and the deformities characteristic of RA does not develop in these other disorders. There are several exceptions to this observation:

●Morning stiffness is common in all inflammatory arthritides. Symmetric arthritis is seen in patients with SLE and can be present in other disorders. Infrequently, nodules similar to those seen in RA may occur in patients with SLE, and other nodular lesions may mimic rheumatoid nodules. (See "Rheumatoid nodules", section on 'Differential diagnosis'.)

●Jaccoud's arthropathy occurs in up to 5 to 10 percent of patients with Sjögren's syndrome or SLE and can also occur in sarcoidosis [ 21]. (See "Musculoskeletal manifestations of systemic lupus erythematosus" and "Sarcoid arthropathy".)

The joint deformities of Jaccoud's arthropathy are not caused by destruction of joints but by loosening and lengthening of periarticular structures and tendons. The ulnar drift or swan neck deformities caused by this disorder resemble RA superficially but can be distinguished by the fact that they are "correctable" on physical examination: fingers with these deformities can be moved manually back into normal alignment. In addition, radiographs in Jaccoud's arthropathy rarely reveal the cartilage loss, erosions, or cysts that are typical of longstanding RA.

Palindromic rheumatism - Palindromic rheumatism is characterized by episodes of joint inflammation sequentially affecting one to several joint areas for hours to days, with symptom-free periods that may last from days to months. Some patients presenting with this syndrome eventually develop a well-defined rheumatic disease, the most common being RA (ranging from 28 to 67 percent); some of the remaining patients develop SLE and other systemic disorders [ 22,23]. Patients with anti-CCP antibodies appear more likely to progress to definite RA [ 24,25]. Close follow-up and specific serologic evaluation can help distinguish among these disorders. (See "Clinical manifestations of rheumatoid arthritis", section on 'Palindromic rheumatism'.)

●The hypermobility syndrome is associated with hyperextensible joints, and patients lack signs of synovitis. (See "Joint hypermobility syndrome".)

●Fibromyalgia is associated with tender points at nonarticular sites and chronic widespread pain. However, there is no evidence of synovitis, such as swelling, warmth, or diminished joint range of motion, although patients may exhibit joint line tenderness on exam. (See "Clinical manifestations and diagnosis of fibromyalgia in adults".)

●Neither the hypermobility syndrome nor fibromyalgia is associated with significant titers of RF or anti-CCP antibodies or with elevated levels of acute phase reactants.

Although RA is normally not difficult to distinguish from fibromyalgia, a significant minority of patients with RA also develop fibromyalgia. The source of complaints in such patients needs to be carefully assessed to distinguish heightened pain sensitivity from pain related to inflammatory joint disease.

The following findings on history, physical examination, or other assessments are more consistent with reactive arthritis than RA:

●History of recent urethritis or enteric infection

●Asymmetric pattern of joint involvement

●Symptoms or signs of enthesopathy (inflammation at the site where a tendon inserts into a bone, eg, the insertion point of the Achilles tendon into the heel)

●Radiologic evidence of sacroiliitis and/or spondylitis

●The presence of human leukocyte antigen (HLA)-B27

Involvement of the hands in reactive arthritis does not pose as great a diagnostic dilemma as that of the knees. Hand arthritis is more commonly asymmetric than in RA. Furthermore, reactive arthritis will often involve not only the joint but also the tenosynovium, entheses, and surrounding tissues of the digit, giving rise to a characteristic "sausage" swelling of the fingers (or toes if the feet are involved) ( picture 1).

The arthritis associated with inflammatory bowel disease (IBD) or other gastrointestinal (GI) disorders is also part of the differential diagnosis. Patients with IBD may develop a peripheral polyarthritis with prominent involvement of the metacarpophalangeal (MCP) joints that can be mistaken for RA; other presentations include predominantly large joint oligoarticular involvement or a spondyloarthropathy with sacroiliitis. This disorder may be missed if abdominal symptoms or symptoms of diarrhea and/or blood or mucus in the stool are not prominent or are not specifically sought in the history. (See "Clinical manifestations and diagnosis of arthritis associated with inflammatory bowel disease and other gastrointestinal diseases".)

The diagnosis of Lyme arthritis can usually be made by serologic testing, which should be performed in patients presenting with undiagnosed inflammatory arthritis in endemic areas. In addition, several clinical features help distinguish Lyme arthritis from RA. Unlike RA, for example, involvement of the small joints of the hands and feet is uncommon in patients with Lyme arthritis. Furthermore, many, but not all, patients with Lyme arthritis will describe an antecedent history of erythema migrans or other early disease manifestations. (See "Musculoskeletal manifestations of Lyme disease", section on 'Laboratory testing'.)

In some patients with a symmetric inflammatory polyarthritis, the only clue to the diagnosis of psoriatic arthritis is a family history of psoriasis. However, in the majority, the findings of skin psoriasis, nail changes (onychodystrophy), sausage toes or fingers, oligoarticular asymmetric large joint or spinal involvement, and/or arthritis mutilans help distinguish the two entities. (See "Clinical manifestations and diagnosis of psoriatic arthritis".)

Polymyalgia rheumatica - Polymyalgia rheumatica (PMR) can sometimes be mistaken for RA in patients presenting with more limited arthritis over the age of 50 who are seronegative or only have a low RF titer. Unlike RA, PMR is usually associated with marked myalgias in the shoulders and hips, and joint involvement tends to be milder, more limited, and more often asymmetric.

Stiffness is thus more axial in PMR and more likely to be described as difficulty getting out of bed, while stiffness in the small joints of the hands and other involved joints predominates in RA, in which difficulty buttoning clothing is more likely to be reported. However, similar complaints to RA may be present in patients with PMR with synovitis affecting the small joints in the hands.

The arthritis in PMR tends to respond strikingly to modest doses of glucocorticoids used to control other symptoms [ 30]. In patients initially diagnosed with PMR, persistent or recurrent small joint arthritis with tapering of glucocorticoids and the absence of other findings suggestive of PMR may lead to a change in the diagnosis to RA after several months or even years of treatment. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica".)

Infectious arthritis - Infectious arthritis is usually monoarticular, but polyarthritis can occur. The diagnosis is established by culturing the pathogen from the synovial fluid or from the blood. Patients with septic arthritis may or may not appear toxic on examination, depending upon the stage of their infection, the presence of medications that can mask infection (eg, glucocorticoids), and other clinical variables. Peripheral blood leukocytosis with a left shift is common but not invariably present.

A low threshold for suspecting infection is required, particularly in compromised hosts. Patients with RA are at increased risk for joint infections because a damaged joint can serve as a nidus of infection. Synovial fluid changes, including marked granulocytosis and low glucose levels, are similar to those seen in RA. (See "Septic arthritis in adults".)

●OA of the fingers typically affects the distal interphalangeal joints and is frequently associated with Heberden's nodes in this area. In contrast, RA typically affects the MCP and proximal interphalangeal (PIP) joints and is not associated with Heberden's nodes.

●The carpometacarpal joint of the thumb is typically involved in OA.

●Swelling of the joints is hard and bony in OA. In contrast, soft, warm, boggy, and tender joints are typical of RA.

●Stiffness of the joint is a very common feature of RA but is relatively uncommon in OA. Furthermore, the stiffness of RA is characteristically worse after resting the joint (eg, morning stiffness), while the stiffness of OA, if present, is typically worse after any effort and is often described as evening stiffness. Morning stiffness in OA, when present, is usually transient or lasts no more than a few minutes, unlike the more sustained stiffness typical of RA.

●Radiographs also help distinguish RA from OA. OA is characterized by narrowing of the joint space due to cartilage loss and osteophytes due to bone remodeling, but not erosions or cysts.

●OA is classically associated with the absence of RFs and normal levels of acute phase reactants. However, RFs may be present, usually in low titer, consistent with the patient's (older) age.

Paraneoplastic disease - Joint pain or frank polyarthritis can occur in association with cancer. The following are some examples:

●Hypertrophic osteoarthropathy - Patients with hypertrophic osteoarthropathy, sometimes termed hypertrophic pulmonary osteoarthropathy, typically demonstrate clubbing of the digits, joint pain, and periosteal new bone formation. Additionally, they give a characteristic history suggestive of bone pain and often describe the pain as deep and achy; nocturnal pain is common. Joint effusions may occur. This is an important diagnosis because lung cancer is the commonest underlying cause. (See "Malignancy and rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)

●Myelodysplasia - Patients with myelodysplastic syndrome sometimes develop an inflammatory polyarthritis that mimics RA [ 31]. The majority of patients are seronegative for RF and few are positive for anti-citrullinated peptide antibody or exhibit erosive changes on joint radiography. The arthritis may precede the diagnosis of myelodysplasia in at least half of the patients. In a cohort study of 87 patients with myelodysplastic syndrome, five (6 percent) had inflammatory arthritis that resembled RA [ 32]. Persistence of anemia, other cytopenias, or elevated acute phase reactants despite control of the arthritis should heighten suspicion of myelodysplasia [ 31]. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)".)

Multicentric reticulohistiocytosis is relatively resistant to glucocorticoids and to disease-modifying antirheumatic drugs (DMARDs) such as methotrexate and hydroxychloroquine. However, there are case reports of response to tumor necrosis factor (TNF)-alpha inhibition [ 35,36] and to parenteral administration of an aminobisphosphonate [ 37,38].

Sarcoid arthropathy - Chronic arthritis in sarcoidosis may be oligoarticular or polyarticular and can appear similar to RA in some patients. It most frequently affects the ankles, knees, hands, wrist, and MCP and PIP joints, and it is frequently associated with parenchymal pulmonary disease.

This disorder is distinguished from RA by the following findings:

●Elevated serum concentrations of angiotensin-converting enzyme (ACE) are found in up to 50 percent of patients.

●A chest radiograph may reveal characteristic findings of sarcoidosis.

●The pattern of acute arthritis with Lofgren's syndrome in patients with sarcoidosis is not observed in those with RA.

(See "Sarcoid arthropathy".)

Due to the rarity of fibroblastic rheumatism, there is no well-established treatment. Progressive disease may lead to sclerodactyly and ankylosis of affected joints.

INFORMATION FOR PATIENTS - UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Rheumatoid arthritis (The Basics)")

●Beyond the Basics topics (see "Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient education: Complementary and alternative therapies for rheumatoid arthritis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The following components of the medical evaluation are helpful in making a clinical diagnosis of RA, both for the identification of characteristic findings and for the exclusion of other diagnoses (see 'Evaluation for suspected RA' above):

*A thorough medical history, with particular attention to joint pain, stiffness, and associated functional difficulties

*A complete physical examination to assess for synovitis, limited joint motion, extraarticular disease manifestations, and signs of diseases included in differential diagnosis

*Basic and selected laboratory testing, including assays for acute phase reactants (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]), rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibodies, and antinuclear antibodies (ANA)

*Selected imaging studies, including bilateral radiographs of the hands, wrists, and feet

*Arthrocentesis, if there is diagnostic uncertainty

●The diagnosis of RA can be made in a patient with inflammatory arthritis involving three or more joints, positive RF and/or anti-citrullinated peptide/protein antibody, disease duration of more than six weeks, and elevated CRP or ESR, but without evidence of diseases with similar clinical features. (See 'Our diagnostic criteria' above.)

●RA may also be diagnosed in patients without all of the classic findings of disease. This includes patients with seronegative RA, those with clinically quiescent disease, and those with recent onset RA. Such patients have findings/clinical features that are generally consistent with those described as meeting the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for RA. (See 'Patients not meeting above criteria' above.)

●The 2010 classification criteria for RA were developed primarily for the identification for research purposes of patients with RA who are at high risk of persistent symptoms and joint injury unless treated with disease-modifying antirheumatic drugs (DMARDs). These criteria have replaced the 1987 criteria, which were based only upon patients with established disease. (See 'Classification criteria' above.)

●The differential diagnosis of RA includes multiple disorders that can generally be distinguished clinically or by limited laboratory testing, based upon a combination of the following features (see 'Differential diagnosis' above):

*Limited duration (eg, in viral arthropathy)

*The presence of other diseases (eg, in psoriatic arthritis or arthritis of inflammatory bowel disease [IBD])

*The pattern of joint involvement and other symptoms (eg, in psoriatic arthritis, spondyloarthropathy, or polymyalgia rheumatica [PMR])

*The presence of systemic features (eg, in systemic lupus erythematosus [SLE] or dermatomyositis [DM])

*Diagnostic laboratory tests associated with other conditions (eg, specific autoantibodies in SLE, synovial fluid crystals in gout or calcium pyrophosphate disease)

*Relatively high specificity of anti-CCP antibodies for RA

ACKNOWLEDGMENT - The editorial staff at UpToDate would like to acknowledge Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS, who contributed to an earlier version of this topic review.

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Diagnosis and differential diagnosis of rheumatoid arthritis - UpToDate

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INTRODUCTION - Rheumatoid arthritis (RA) is a symmetric, inflammatory, peripheral polyarthritis of unknown etiology. It typically leads to deformity through the stretching of tendons and ligaments and destruction of joints through the erosion of cartilage and bone.

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Here is our presentation for RA :)