ALL-RUSSIAN NON-GOVERNMENTAL ORGANIZATION
"ASSOCIATION OF RHEUMATOLOGISTS OF RUSSIA"
ASSOCIATION OF RHEUMATOLOGISTS OF RUSSIA
ON DIAGNOSIS AND TREATMENT OF RHEUMATOID ARTHRITIS
2. Definition, diagnostic principles, features of the early stage of RA
2.1. Diagnostic criteria for RA
2.2. Instrumental diagnostics for RA
2.3. Differential diagnosis of RA
4. The role of the general practitioner in the management of patients with RA
5. Patient education
Methods used to collect/select evidence:
Search in electronic databases. The evidence base for the Recommendations are publications included in the Cochrane Library, EMBASE and MEDLINE databases. Search depth 5 years.
Methods used to assess the quality and strength of evidence:
· Assessment of the level of evidence in accordance with the rating scheme (Table 2)
Rating scheme for assessing the significance of a publication
A high-quality meta-analysis, systematic review of RCTs, or large RCTs with a very low likelihood of bias, the results of which can be generalized to a relevant Russian population.
High-quality review or systematic review of cohort or case-control studies or
A high-quality cohort or case-control study with very low levels of bias, or
An RCT with a low risk of bias, the results of which can be generalized to the relevant Russian population.
A cohort study or a case-control study or a controlled study without randomization with a low level of systematic error, the results of which can be generalized to the relevant Russian population or
RCTs with a very low or low risk of bias, the results of which cannot be generalized to the relevant Russian population.
Case series description or
Uncontrolled study or
RCT – randomized clinical trials
Description of methods used to analyze evidence:
The selection of a publication as a potential source of evidence-based information occurred after studying the methodology used in the work to determine its validity and level of evidence.
The development of the Guidelines complies with international standards set out in the AGREE (Appraisal of Guidelines Research and Evaluation) questionnaire and the recommendations of the Guidelines International Network (GIN).
Good Practice Points ( GPPs ):
The GPPs are based on the clinical experience of the experts in the working group that developed these Guidelines.
No cost analysis was performed and pharmacoeconomics publications were not reviewed.
2. Definition, principles of diagnosis.
Rheumatoid arthritis (RA) is an autoimmune rheumatic disease of unknown etiology, characterized by chronic erosive arthritis (synovitis) and systemic damage to internal organs. The prevalence of RA among the adult population is 0.5–2% (in women 65 years old, about 5%). The ratio of women to men is 2–3:1. All age groups are affected, including children and the elderly. The peak onset of the disease is 40–55 years. No screening is carried out. RA is characterized by a variety of variants of onset of the disease. In most cases, the disease begins with polyarthritis, less often with mono- and oligoarthritis, sometimes the manifestations of arthritis can be moderate, and arthralgia, morning stiffness in the joints, deterioration in general condition, weakness, weight loss, low-grade fever, lymphadenopathy predominate, which may precede clinically significant joint damage.
Among patients with new-onset inflammatory joint disease there are:
Very early RA - a condition with a duration of symptoms of 3-6 months (potentially reversible condition)
· Early RA, or “early established RA” – the first 1-2 years of the disease (when the first signs of disease progression can be determined, such as the presence or absence of a typical erosive process in the joints)
· Undifferentiated arthritis (currently the term “undifferentiated peripheral arthritis” - UPA) is an inflammatory lesion of one or joints that cannot be attributed (at the moment) to any specific nosological form, that is, not meeting the classification criteria for RA or any other disease. About 1/3 of patients with NPA develop RA within 1 year of follow-up.
In the presence of a classic clinical picture, especially with a typical lesion of the hand, the diagnosis of RA is not difficult. The problems of early diagnosis of RA are as follows:
- the classic clinical picture is observed, as a rule, in patients with long-term RA, and at the onset of the disease a number of typical clinical (for example, ulnar deviation of the fingers and rheumatoid nodules), immunological (rheumatoid factor) and radiological (bone erosions) symptoms may be absent ;
— the onset of RA is characterized by pronounced heterogeneity of symptoms;
— with RA there are no truly pathognomonic symptoms;
The group of patients with UPA is the most difficult in diagnostic terms, since these patients require dynamic observation and repeated examinations to verify the diagnosis. Based on clinical practice, all patients with RA and suspected RA are divided into the following diagnostic groups (the corresponding ICD10 codes are indicated in brackets):
· Rheumatoid arthritis, seropositive (M05.8)
· Rheumatoid arthritis seronegative (M06.0)
· Probable rheumatoid arthritis (M05.9, M06.4, M06.9)
Undifferentiated arthritis (M13.0, M13.1, M13.8, M13.9)
Due to the fact that the diagnosis of RA must be verified by a rheumatologist, the key factor in early diagnosis is the earliest possible referral of the patient to a rheumatologist. For general practitioners, it is recommended to use the EULAR Clinical Suspicion Criteria for RA to select patients for consultation with a rheumatologist (modified):
· swelling of at least one peripheral joint reliably determined upon examination
positive symptom of “squeezing” of the hands and/or feet
morning stiffness lasting 30 minutes or more.
2.1. Diagnostic criteria and differential diagnosis of RA
To verify the diagnosis, it is recommended to use the 2010 ACR/EULAR Classification Criteria for Rheumatoid Arthritis (American College of Rheumatology/European League Against Rheumatism Rheumatoid arthritis classification criteria).
In order to make a diagnosis of RA according to the new criteria, the doctor must fulfill three conditions.
· determine whether the patient has at least one swollen joint based on physical examination.
· exclude other diseases that may be accompanied by inflammatory changes in the joints.
· score at least 6 points out of 10 possible on 4 items describing the features of the disease picture in a given patient (Table 1).
Table 1. Classification criteria of the RA ACR/EULAR 2010
A. Clinical signs of joint damage (swelling and/or pain on objective examination) (0-5 points)
1 large joint
-2-10 large joints
– 1-3 small joints (large joints are not taken into account)
– 4-10 small joints (large joints are not taken into account)
— >10 joints (at least 1 small joint)
B. RF and ACCP tests (0-3 points, at least 1 test required)
— Weakly positive for RF or ACCP (exceeds the upper limit of normal, but not more than 3 times)
— Highly positive for RF or ACCP (more than 3 times the upper limit of normal)
C. Acute phase score, at least 1 test required)
— Normal values of ESR and CRP
— Increased ESR or CRP
D. Duration of synovitis (0-1 point)
RF – rheumatoid factor
ACCP – antibodies to cyclic citrullinated peptide
ESR – erythrocyte sedimentation rate
CRP – C-reactive protein
The main place is occupied by the characteristics of joint damage. It is based on determining the number of inflamed joints. In this case, in contrast to the 1987 ACR classification criteria, not only swelling of the joint, but also its pain during an objective examination are taken into account as signs that allow the presence of synovitis to be recorded. Assessment of the patient's status within the framework of the new criteria is based on the identification of 4 categories of joints (Table 2).
Table 2. Categories of joints in the 2010 ACR/EULAR RA criteria.
— Changes in the distal interphalangeal joints, first carpometacarpal joints and first metatarsophalangeal joints are not taken into account
— Shoulder, elbow, hip, knee, ankle
— Metacarpophalangeal, proximal interphalangeal, 2-5 metatarsophalangeal, interphalangeal joints of the thumbs, wrist joints
— Joints that may be affected by RA, but are not included in any of the groups listed above (for example, temporomandibular, acromioclavicular, sternoclavicular, etc.)
Three categories of patients are particularly distinguished: they do not meet the criteria at the time of examination, but for whom, nevertheless, a reliable diagnosis of RA can be established.
1. Patients who have erosions typical of RA on radiographs. The erosive lesions characteristic of RA are well described in many monographs, atlases and manuals, however, there is still no clear definition of “erosion typical of RA”. Therefore, significant personal experience of the rheumatologist and radiologist may be required for a reliable diagnosis.
2. Patients with a significant history of RA who previously met the diagnostic criteria for this disease.
3. Patients with early stage RA who do not meet criteria at baseline but become eligible as the disease progresses during follow-up. If the number of points for a diagnosis of RA is insufficient, the assessment can be carried out repeatedly and cumulatively (that is, taking into account all changes identified during the observation period).
A separate category are patients with NPA, who for a long time may not meet the criteria for RA (or any other specific nosological form). In this case, it is necessary to assess the prognosis in terms of the development of RA or other pathology. The main factor of an unfavorable prognosis for the development of RA is the detection of anti-citrullinated antibodies in the patient (primarily antibodies to cyclic citrullinated peptide - CCCP).
Instrumental research methods are not included in the criteria for the diagnosis of RA, but are widely used for the following purposes:
· identification of early structural damage, which makes it possible to clarify the diagnosis in cases where the criterion assessment does not give clear results
· verification of the diagnosis of RA at a late stage of the disease, when the activity of the inflammatory process may spontaneously decrease and the phenomena of osteochondral destruction predominate
· assessment of the rate of progression of structural damage for prognostic purposes
Monitoring response to therapy
· verification of structural disorders before orthopedic-surgical treatment and orthotics
To confirm the diagnosis, establish the stage and assess the progression of joint destruction in RA, plain radiographs of the hands and distal feet (DOS) are required. Survey radiographs of the hands and DOS are recommended to be performed during the initial examination and then annually for all patients with RA . For patients in the late stage of RA (see section 2.5), with Steinbrocker stages 3 and 4, repeat radiography of the hands and DOS is performed less frequently, the frequency is determined by the specific clinical situation.
RA is characterized by multiplicity and symmetry of damage to small joints of the hands and joint pain. The initial manifestations of the disease should be looked for in joints typical for RA:
1. Early radiological symptoms of arthritis are found: in the 2nd and 3rd metacarpophalangeal joints; 3 proximal interphalangeal joints; in the joints of the wrists; wrist joints; styloid processes of the ulna bones; 5 metatarsophalangeal joints.
2. Typical for RA are symmetrical radiological changes in the metacarpophalangeal joints, proximal interphalangeal joints; in the joints of the wrists; metatarsophalangeal joints and 1st interphalangeal joints of the feet
3. With more pronounced radiological stages of RA (Steinbrocker stages 3 and 4), changes can be detected in the distal interphalangeal joints of the hands and proximal interphalangeal joints of the feet.
4. RA does not begin with damage to the distal interphalangeal joints of the hands and feet; proximal interphalangeal joints of the feet
5. Bone ankylosis in RA is detected only in the intercarpal joints; 2-5 carpometacarpal joints and, less often, in the tarsal joints.
There are no radiological changes characteristic of RA in the large joints of the upper and lower extremities and in the joints of the axial skeleton. Radiological symptoms of arthritis in this group of joints are nonspecific and may be found in other rheumatic diseases. In this regard, radiography of large joints in RA is not recommended as a routine method and is performed only if there are specific indications (suspicion of avascular necrosis, etc.).
To determine the radiological stage, the modified Steinbrocker classification of RA is used:
Stage I - periarticular osteoporosis; single cysts
Stage II - periarticular osteoporosis; multiple cysts; narrowing of the joint space, there may be single erosions (1-4);
Stage III – stage II symptoms + multiple erosions (5 or more) + dislocations or subluxations in the joints;
Stage IV - stage III symptoms + bone ankylosis.
Form of the disease: nonerosive; erosive.
Timing of appearance of the main radiological symptoms of RA:
1. With an acute onset and active course of RA, periarticular osteoporosis and single cysts can be detected within 1 month of the disease; multiple cysts and narrowing of joint spaces from 3 to 6 months; first erosion within 1 year of disease
2. More typical is the appearance of the first symptoms several months (up to 1 year) from the onset of the disease; erosion for 2-3 years from the onset of the disease
3. Bone ankylosis of the wrist joints can be detected after 10 years or more (depending on the course of erosive arthritis in the wrist joints)
Features of the course of RA in terms of the dynamics of development of radiological changes:
1. In the classic course of RA, erosions in the joints cannot precede periarticular osteoporosis, cysts and narrowing of joint spaces in the joints of the hands and joints.
2. Bone ankylosis in RA does not form in the interphalangeal, metacarpophalangeal and metatarsophalangeal joints of the hands and joints, in the 1st carpometacarpal joints. RA is characterized by ankylosis of the intercarpal, carpometacarpal joints and, less commonly, the tarsal joints.
Chest x-ray is indicated in all patients to identify rheumatoid
lesions of the respiratory system and concomitant lesions of the lungs (for example, tuberculosis, COPD, etc.) during the initial examination and then annually (more frequent examination should be justified by the clinical situation).
Computed tomography of the lungs is advisable if there is clinical suspicion of:
RA-related diffuse (interstitial) or focal (rheumatoid nodes) lung damage
disease of the chest organs, which may cause joint damage during the differential diagnosis of RA (sarcoidosis, malignant neoplasms, etc.)
· concomitant pathology that may affect the choice of therapy or is an undesirable reaction to treatment (tuberculosis, methotrexate pneumonitis, etc.)
Magnetic resonance imaging (MRI).
MRI is a more sensitive method for detecting synovitis at the onset of RA than standard joint radiography. MRI symptoms of arthritis are nonspecific. Similar MRI changes may be present in other inflammatory joint diseases and in clinically “normal” joints. Changes detected by MRI (synovitis, tenosynovitis, bone marrow edema and bone erosion) make it possible to predict the progression of joint destruction. MRI of the hands is indicated for patients with early RA and PAD.
Ultrasound examination (ultrasound) of joints is used in 2 main types:
· UI of large joints
Ultrasound of the joints evaluates:
· on the “gray scale” - thickening of the synovial membrane, the presence of effusion in the joint, disruption of the contour of the articular surface (corresponds to erosion), changes in the periarticular tissues (tenosynovitis)
· with a power Doppler study - localization, extent and intensity of the signal, which allows us to judge the severity of proliferative inflammation.
Ultrasound of the hand has diagnostic and prognostic value in early RA, and also allows one to assess the depth of remission during antirheumatic therapy. Currently, there is insufficient evidence to consider ultrasound a more accurate method than careful clinical examination of the joints.
The use of MRI and ultrasound of the joints provides valuable additional data, but the assessment of the results of these studies is not sufficiently standardized, and therefore, at present, it cannot be recommended to substantiate the diagnosis or make treatment decisions based on data from these studies alone , without an appropriate clinical and laboratory basis.
2.4. Methods for assessing RA activity
In RA, there is no single symptom that can reliably assess disease activity. The main method for objectifying inflammatory activity is the use of complex activity indices.
It is recommended to use the following indices:
· DAS28 – disease activity score (Disease Activity Score) for 28 joints (modified using ESR and CRP)
SDAI – Simplified Disease Activity Index
CDAI - Clinical Disease Activity Index
All of the above indices are based on the following main clinical and laboratory indicators:
· number of swollen joints (SJS) and number of painful joints (PJS) out of 28 (the wrist, metacarpophalangeal, proximal interphalangeal, shoulder, elbow, knee joints are taken into account)
· general assessment of the severity of symptoms on a 100-mm horizontal visual analogue scale: general assessment of disease activity by the physician (GAAD) and general assessment of the patient’s health state (GASA)
· ESR in mm per hour (mm/h) according to the Westergren method
· CRP in blood serum, determined by quantitative method.
Formula for calculating DAS28:
Assessment of disease activity using DAS28:
0 = remission (DAS28 < 2.6)
1 = low (2.6< DAS28 <3.2)
2 = average (DAS28 3.2 - 5.1)
3 = high (DAS28 > 5.1)
Tab. 3. Assessment of response to therapy using the DAS28 index
Decrease DAS 28
Formula for calculating SDAI:
Notes: 1) OOAV and OOSB are approximated to a scale from 0 to 10; 2) CRP is measured in mg/dL
Assessment of activity and response to therapy according to SDAI:
• Low activity 3.3-11
• Moderate activity 11.1-26
• High activity > 26
Evaluation of response to therapy:
• Moderate response - SDAI reduction by 7 points
• Significant response – 17 point reduction in SDAI
Formula to calculate CDAI:
Notes: 1) OOAV and OOSB are approximated to a scale from 0 to 10
High activity > 22
Moderate activity 10 – 22
Low activity 2.8 – 10
• Moderate response—decrease in CDAI by 7 points
• Significant response – 17 point reduction in CDAI.
2.5. Clinical classification of RA
Classification of rheumatoid arthritis (adopted at the meeting of the Plenum of the Association of Rheumatologists of Russia on September 30, 2007)
1. Main diagnosis:
n Rheumatoid arthritis, seropositive (M05.8)
n Rheumatoid arthritis seronegative (M06.0)
n Special clinical forms of rheumatoid arthritis:
q Felty's syndrome (M05.0)
q Adult-onset Still's disease (M06.1)
n Rheumatoid arthritis probable (M05.9, M06.4, M06.9)
2. Clinical stage:
n Very early stage: disease duration < 6 months
n Early stage: disease duration 6 months. - 1 year
n Advanced stage: disease duration > 1 year in the presence of typical RA symptoms
n Late stage: disease duration of 2 years or more + pronounced destruction of small (III-IV X-ray stage) and large joints, presence of complications
3. Disease activity:
n 0 = remission (DAS28 < 2.6)
n 1 = low (2.6< DAS28 <3.2)
n 2 = average (DAS28 3.2 - 5.1)
n 3 = high (DAS28 > 5.1)
4. Extra-articular (systemic) manifestations:
1. rheumatoid nodules
2. cutaneous vasculitis (ulcerative necrotizing vasculitis, nail bed infarctions, digital arteritis, livedoangiitis)
3. vasculitis of other organs
4. neuropathy (mononeuritis, polyneuropathy)
5. pleurisy (dry, effusion), pericarditis (dry, effusion)
6. Sjögren's syndrome
7. eye damage (scleritis, episcleritis, retinal vasculitis)
5. Instrumental characteristics:
· Presence of erosions (using radiography, possibly MRI, ultrasound):
X-ray stage (according to Steinbrocker, modification):
I - periarticular osteoporosis
II – osteoporosis + narrowing of the joint space, there may be single erosions
III – signs of the previous stage + multiple erosions + subluxations in the joints
IV – signs of the previous stage + bone ankylosis
6. Additional immunological characteristics - anti-citrullinated antibodies:
7. Functional class:
I – fully preserved: self-service, non-professional and professional activities
II – preserved: self-service, professional activities, limited: non-professional activities
III – preserved: self-service, limited: non-professional and professional activities
IV – limited: self-service, non-professional and professional activities
1. secondary systemic amyloidosis
2. secondary arthrosis
3. osteoporosis (systemic)
5. tunnel syndromes (carpal tunnel syndrome, compression syndromes of the ulnar and tibial nerves)
6. subluxation in the atlantoaxial joint, including with myelopathy, instability of the cervical spine
Comments on the RA Classification:
1. To the heading “Main diagnosis”:
Seropositivity and seronegativity are determined by a rheumatoid factor test, which must be performed using a reliable quantitative or semi-quantitative test (latex test, enzyme immunoassay, immunonephelometric method).
2. To section 3 “Disease activity”:
a) It is recommended to use the DAS28 index as a basic method for assessing activity.
Formula for calculating DAS28:
where NBS is the number of painful joints, NPS is the number of swollen joints from the following 28: shoulder, elbow, wrist, metacarpophalangeal, proximal interphalangeal, knee,
ESR – erythrocyte sedimentation rate according to the Westergren method,
OSHA – general assessment of the patient’s health status in mm on a 100 mm visual analogue scale
b) It is acceptable to use other methods for calculating activity, for which good comparability with DAS28 has been proven
2. To rubric 5 “Instrumental characteristics”:
Detailed characteristics of radiological stages:
Stage 1. Minor periarticular osteoporosis. Single cyst-like clearings of bone tissue. Slight narrowing of the joint spaces in individual joints.
Stage 2 . Moderate (severe) periarticular osteoporosis. Multiple cyst-like clearings of bone tissue. Narrowing of joint spaces. Single erosions of articular surfaces (1-4). Minor bone deformities.
Stage 3 . Moderate (severe) periarticular osteoporosis. Multiple cyst-like clearings of bone tissue. Narrowing of joint spaces. Multiple erosions of articular surfaces (5 or more). Multiple severe bone deformities. Subluxations and dislocations of joints.
Stage 4 . Moderate (severe) periarticular (widespread) osteoporosis. Multiple cyst-like clearings of bone tissue. Narrowing of joint spaces. Multiple erosions of bones and articular surfaces. Multiple severe bone deformities. Subluxations and dislocations of joints. Single (multiple) bone ankylosis. Subchondral osteosclerosis. Osteophytes on the edges of the articular surfaces.
3. To section 7 - Description of characteristics to determine the functional class:
· Self-care : dressing, eating, grooming, etc.
· Non-professional activities : elements of rest, leisure, sports, etc., taking into account gender and age
· Professional activity : work, study, housekeeping (for housekeepers), taking into account gender and age.
Examples of formulation of clinical diagnoses:
· Rheumatoid arthritis, seropositive (M05.8), advanced stage, activity II, erosive (radiological stage II), with systemic manifestations (rheumatoid nodules), ACCP (-), FC II.
· Rheumatoid arthritis seronegative (M06.0), early stage, activity III, non-erosive (X-ray stage I), ACCP (+), FC I.
· Rheumatoid arthritis, seropositive (M05.8), late stage, erosive (radiological stage III), activity II, with systemic manifestations (rheumatoid nodules, digital arteritis), ACCP (? - not studied), FC III, complications - carpal tunnel syndrome on the right, secondary amyloidosis with kidney damage.
· Probable rheumatoid arthritis (M06.9), seronegative, early stage, activity II, non-erosive (radiological stage I), ACCP (+), FC I.
1. The main goal of pharmacotherapy for RA is to achieve remission (or low activity) of the disease (A) , as well as reduce the risk of comorbid diseases (C).
2. Treatment of patients with RA should be carried out by rheumatologists (as an exception, a general practitioner, but with the advisory support of a rheumatologist) with the involvement of specialists from other medical specialties (orthopedists, physiotherapists, cardiologists, neurologists, psychologists, etc.) and be based on close interaction between doctor and patient (C).
3. Patients should be advised to avoid factors that can provoke exacerbation of the disease (intercurrent infections, stress, etc.), quit smoking, and strive to maintain normal body weight (C).
4. The main place in the treatment of RA is occupied by drug therapy: nonsteroidal anti-inflammatory drugs (NSAIDs), simple analgesics, glucocorticoids (GCs), synthetic disease-modifying anti-inflammatory drugs (DMARDs) and targeted therapy, which are currently represented by genetically engineered biological drugs (GEBPs). ) (A). Non-drug therapies are in addition to medications and are used in certain groups of patients for specific indications.
5. To reduce joint pain, NSAIDs are used, which have a good symptomatic (analgesic) effect, but do not affect the progression of joint destruction, the prognosis of the disease and can cause severe adverse reactions (AR) from the gastrointestinal tract and cardiovascular system (A) . To reduce the risk of ADR, the use of NSAIDs in RA should be limited as much as possible.
6. Treatment with GCs (low/moderate doses) is recommended in combination with DMARDs as a component of combination therapy for RA, to relieve exacerbations before the effect of DMARDs develops (bridge therapy) or as monotherapy if DMARDs and biologically active drugs are ineffective (or impossible); Taking GC is accompanied by the development of side effects that require careful monitoring (A) . The use of GCs in RA should be limited to strict indications and carried out by rheumatologists.
7. DMARD therapy should be administered to all patients with RA without exception and prescribed as early as possible (within 3-6 months from the onset of symptoms of the disease) (A)
8. During the treatment process, the effectiveness of therapy should be carefully monitored (every 1-3 months), the treatment regimen should be “selected” depending on the activity of the disease (A); The effect of DMARDs and biologically active drugs on the progression of joint destruction should be assessed every 6-12 months in early RA (B) and every 12 months in advanced RA and taken into account when choosing therapy, regardless of its clinical effectiveness (C).
9. When choosing therapy with DMARDs and GEBD, it is necessary to take into account the duration of the disease (< 6 months - early stage; > 6 months - advanced stage) and the presence of unfavorable prognosis factors (rheumatoid nodules, vasculitis, Felty's syndrome, positive results of determining RF and ACCP, as well as an increase in ESR and CRP) (C).
Treatment with standard DMARDs
10. Methotrexate (MTX) is the “first-line” drug for the treatment of RA with proven efficacy and safety (A ). In patients new to MTX treatment, the efficacy/safety/cost ratio favors MTX monotherapy compared with combination therapy of MTX and other standard DMARDs and GEDM monotherapy (A).
11. If there are contraindications (or poor tolerance) for prescribing MT, leflunomide, sulfasalazine (A) should be prescribed.
12. Before prescribing MT, one should assess the risk factors for adverse reactions (AR) (alcohol intake), examine laboratory parameters (AST, ALT, albumin, complete blood count, creatinine, glucose, lipids, pregnancy test), markers of viral infections (HIV, hepatitis B/C) perform a chest x-ray (C) ; patients should be informed about the benefits of therapy and possible adverse reactions (B)
13. MTX treatment should begin at a dose of 10-15 mg/week and increase by 5 mg every 2-4 weeks up to 20-30 mg/week depending on effectiveness and tolerability (B).
14. In case of insufficient effectiveness and tolerability (not severe adverse events) of oral MTX, it is advisable to prescribe a parenteral (subcutaneous) form of the drug (B).
15. During treatment with MT, it is mandatory to take at least 5 mg of folic acid per week. (A)
16. At the beginning of treatment or when increasing the dose of MT, determination of ALT/AST, creatinine, and a general blood test must be performed every 1-1.5 months until a stable dose of MT is achieved, then every 3 months; Clinical assessment of ADRs and risk factors should be performed at each patient visit (C). MTX treatment should be interrupted when ALT/AST concentrations increase > 3 upper limit of normal (ULN); resume treatment at a lower dose after normalization of parameters. If there is a persistent increase in AST/ALT levels > 3 ULN, the dose of MT should be adjusted; If the increase in AST/ALT levels > 3 ULN persists after discontinuation of MT, appropriate diagnostic procedures should be performed. (C)
17. In patients with early RA who have risk factors for poor prognosis, high disease activity, and are resistant to MTX monotherapy, it is advisable to prescribe combination therapy with MTX and other standard DMARDs - leflunomide, sulfasalazine and gadroxychloroquine (C).
18. Combination therapy with MT and LEF should be carried out with caution due to the high risk of developing adverse reactions (gastroenterological and hepatic) (B) ; Combination therapy with MTX and LEF has no advantages over combination therapy with MTX and other standard DMARDs.
19. For the treatment of RA, genetically engineered biological drugs are used - biological drugs (see Table 4), which include TNF-a inhibitors (infliximab - INF, adalimumab - ADA, etanercept - ETC, certolizumab pegol - CTZ, golimumab - GLM) , anti-B cell drug - rituximab (RTM), costimulation blocker of T - lymphocytes - abatacept (ABC) and interleukin 6 receptor blocker - tocilizumab (TCZ) (A).
20. The use of GEBD is recommended in case of insufficient effectiveness (moderate/high disease activity), monotherapy with MTX or combination therapy with MTX and other DMARDs, which should be used in adequate doses for ≥ 3 months. The drugs of choice are TNF-a inhibitors, which have similar efficacy and toxicity (level of evidence A-C).
21. To increase the effectiveness of therapy and reduce the immunogenicity of a number of drugs, it is advisable to combine biologic drugs with the use of MTX (A).
22. In patients with intolerance to MT, monotherapy with TNF-a inhibitors (ADA, ETC, CZP), IL-6R blocker (TCZ) or combination therapy with GIBD and other standard DMARDs is possible (B).
23. If the first TNF-a inhibitor is insufficiently effective, it is advisable to prescribe a GIBP with other mechanisms of action (ABC, RTM, TCZ) (A), another TNF-a inhibitor or MTX (in patients who have not received MTX) (B)
24. If the effectiveness of 2 TNF-a inhibitors is insufficient, a GIBD with other mechanisms of action (ABC, RTM, TZC) should be prescribed. (V/C).
(A) inhibitors, may be prescribed as the first BD
26. It is advisable to prescribe RTM to RA patients who are seropositive for RF and/or ACCP, have extra-articular manifestations of RA or a combination with other autoimmune disorders, or have contraindications for the prescription of TNF-a inhibitors ; To maintain the effect, repeated courses of RTM are necessary 6 months after the previous course (B).
27. In patients resistant to ABC, RTM or TCZ, the following therapeutic solutions are possible: prescribing any previously unused GEBD or DMARD; use of new antirheumatic drugs. In cases of multidrug resistance, combination therapy with RTM and TNF-a inhibitors may be considered, as RCT data suggest the effectiveness and acceptable toxicity of combination therapy with RTM (low doses) and TNF-a inhibitors (ETC and ADA) (C).
28. Upon achieving stable remission lasting at least 6 months, gradual withdrawal of NSAIDs and then GCs may be recommended (following existing recommendations for dose titration). After discontinuation of GCs and NSAIDs, a gradual, carefully controlled cessation of GIBP treatment is possible. If stable remission is maintained, it is possible to reduce the dose and gradually discontinue DMARDs as a joint decision between the rheumatologist and the patient. In case of insufficient stability of remission, DMARDs are prescribed indefinitely, including for life (B/C).
First published online on December 15, 2016.
Objectives Guidelines for early arthritis were first introduced in 2007, but significant research has been carried out in recent years.
Methods 20 rheumatologists, 2 patients and 1 physician from a total of 12 European countries contributed to the preparation of the guidelines. A systematic literature review (SLR systematic literature research) was completed by two fellows with the assistance of a qualified librarian. A set of draft recommendations was proposed based on the research questions and SLR findings. For each of these recommendations, categories of evidence were determined, the strength of the recommendations was obtained, and the level of agreement was determined through a voting process.
Results The updated guidelines include 3 general principles and 12 recommendations for the management of early arthritis. Selected statements include arthritis definition, referral, diagnosis, prognosis, treatment (information, education, pharmacological and non-pharmacological interventions), monitoring and strategies. Eighteen topics were identified for future research.
Conclusions These recommendations are prepared for rheumatologists, general practitioners, health and social care workers, patients and other stakeholders on the updated EULAR consensus on the overall management of early arthritis:
Peripheral inflammatory arthritis is one of the most common diseases of patients in clinical rheumatology. Diagnosing the underlying disease can be difficult, especially at an early stage. In clinical practice, early inflammatory arthritis is often undifferentiated. Early arthritis may develop into established rheumatoid arthritis (RA) or other defined arthropathy, may resolve spontaneously, or may remain undifferentiated for an indefinite period of time. To better assess the diagnosis and outcome of arthritis, it has been suggested that inflammatory arthritis should first be recognized; then searching for a specific diagnosis (eg, peripheral or axial spondyloarthritis; psoriatic arthritis (PsA); systemic lupus erythematosus, etc) and, finally, assessing the risk of developing persistent and/or erosive arthritis and suggesting the optimal therapeutic strategy. Although the prognosis of early arthritis is still difficult to determine, a combination of clinical, laboratory, and radiographic parameters can help predict patient outcomes with reasonable accuracy.
Approaches to early arthritis have changed significantly in recent years, influenced by new concepts for diagnosis and new effective treatments. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) have been shown to slow disease progression in chronic inflammatory arthritis such as RA and PsA. In addition, biological (b)DMARDs have shown rapid and sustained effects associated with the suppression of joint destruction. A large body of evidence indicates the usefulness of very early DMARD therapy for early chronic inflammatory arthritis, preferably before the onset of erosions, in order to reduce or even prevent the risk of further onset joint destruction and disability. In addition, evaluation and ongoing monitoring of patients with early arthritis serves to better tailor therapeutic strategies. Without a doubt, the goal of treatment for early arthritis should now be to achieve clinical remission and prevent joint destruction.
Patients with early arthritis should be identified and referred to rheumatologists to confirm the presence of arthritis, the (potential) diagnosis and its prognosis, and initiate appropriate treatment based on these recommendations. Additionally, management of early arthritis should include more than just drug therapy, with education, shared decision making, and collaboration with social workers as an important topic.
A set of recommendations for arthritis management should include all of these different aspects.
In 2007, the European League Against Rheumatism (EULAR) guidelines for the management of early arthritis were published. In 2010, EULAR introduced recommendations for the management of RA with synthetic and biological DMARDs, which were updated in 2013 and 2016. In addition, recommendations regarding the management of PsA have recently been published. Although recent recommendations have focused on pharmacological treatment of PsA and RA, both in advanced and early stages of the disease, the 2007 recommendations for the management of early arthritis cover the entire spectrum of management of early arthritis, including arthritis diagnosis, evaluation, diagnosis, prognosis, classification, information, education and non-pharmacological interventions and monitoring of the pathological process, as well as drug treatment. A systematic literature review (SLR) passed the EULAR 2007 guidelines included publications up to January 2005. Between 2005 and 2015, research on early arthritis was a major focus, and numerous studies appeared in the literature. This literature includes, but is not limited to, topics such as diagnostic and classification criteria, window of opportunity, imaging, prognosis, treatment, and therapeutic strategies.
Updated EULAR recommendations for the management of early arthritis are consistent with the 2014 EULAR standard guidance. Definitions (eg, management and early arthritis) and target populations (rheumatologists, general practitioners, medical students, healthcare workers, patients) selected by the 2007 Expert Committee. In short , the term "management" was defined as "all organizational, diagnostic, medical and educational procedures relating to patients seeking care for arthritis of peripheral joints" and "early arthritis" was limited to "early inflammatory joint disease."
The expert committee consists of 20 rheumatologists, including 2 researchers (CID and CH), 1 physician and 2 patients, from 12 European countries.
Data-driven approach
The research questions were adjusted from the literature review as necessary and structured according to patients-intervention-comparator-outcomes categorized by four authors (CID, CH, BC, RL). (convenor (BC) methodologist (RL)) The types of relevant studies were also identified.
A systematic search of PubMed, Medline, Embase, CINAHL and the Cochrane Library was performed with the help of a qualified librarian (Louise Falzon, Columbia University Medical Center, USA). All articles published in English before December 2015 were included. Excerpts from the 2014 and 2015 EULAR and American College of Rheumatology (ACR) Conferences were also reviewed. The search was completed by hand searching and interviewing experts for additional references. The SLR process is detailed in two separate articles.
Expert opinion approach
Each Expert Committee member received a presentation of the results of the literature search and accompanying levels of evidence prior to the January 2016 meeting. During the meeting, the results of the SLR were presented to the Committee in an aggregated form. Three break-out groups, chaired by one expert, formed amendments to the 2007 recommendations (1 – 4; 5 – 8 and 9 – 12) and proposed new recommendations if deemed appropriate. Each group then presented their proposals and language to the full Committee for discussion and consensus, and the final wording of the recommendations was reached after voting with less than 85% agreement on the final wording of each element.
Following the meeting, recommendations were sent by email to all Expert Committee members for additional minor amendments, if necessary. Categories of evidence and recommendation scores were then determined (CID, CH, RL, BC) according to Oxford Center for Evidence-Based Medicine standards. To determine the level of agreement with recommendations, anonymized based on an email vote on a scale of 0–10 performed, with a vote of 0 indicating complete disagreement with a particular recommendation and 10 indicating complete agreement. Means and SDs for scores from the entire group were calculated. Recommendations are presented in BOX 1 box and in Figure 1.
Algorithms based on the 2016 updated recommendations of the European League Against Rheumatism for the management of early arthritis.
* Combination with glucocorticoids is preferable.
†Reduction of disease activity may be an alternative goal in rare cases.
‡Should also include weight loss, smoking cessation, dental care and vaccinations.
ACPA, anticitrullinated peptide antibody; DMARDs, Disease Modifying Antirheumatic Drugs; NSAIDs, non-steroidal anti-inflammatory drugs, RF, rheumatoid factor.
As a result of the discussion of the Committee experts, 3 general principles and 12 recommendations were formulated (Box 1) (in 2007, 12 recommendations were formulated).
The Expert Committee believes that some of the principles concerning the care of patients with early arthritis are universal and should be stated first and separated from individual recommendations for diagnosis, prognosis and treatment. The Committee unanimously agreed on the following three general principles (Box, box 1).
The term "best care" is obviously one of the basic principles in the field of medicine. The wording “shares the decision between the patient and the rheumatologist” is more than informing the patient; rather, it is a comprehensive process of communication, knowledge sharing, and consensus building that should lead to a discussion of treatment options that are optimal from the patient's and clinician's perspective.
This statement, which is part of recommendation 1 in the 2007 guidelines, was also emphasized in the EULAR guidelines for the management of RA and PsA. Its basis is evidence that patients with chronic arthritis, when seen by a rheumatologist, receive an earlier diagnosis, start treatment earlier and have better outcomes, particularly in terms of joint damage and physical function. Rheumatologists have the experience to make an accurate diagnosis of early arthritis, are familiar with monitoring disease activity and the potential severity of disease in their patients with inflammatory arthritis, and are familiar with the indications, contraindications, and adverse effects of specific treatments.
However, the Expert Committee intentionally added the term “principally” to this statement for three reasons: (1) Management of patients with early arthritis begins with primary care physicians and other health care providers in a multidisciplinary approach; (2) in some areas, help from rheumatologists is not always available. Some countries have a shortage of rheumatologists, and in such situations, patients should receive treatment from other health care providers with experience in caring for patients with inflammatory arthritis; (3) in some countries, the goal of transition from rheumatologists to other medical specialists is actively promoted with the aim of facilitating access and optimal quality of care and making follow-up cheaper. Such care should preferably remain primarily under the responsibility and supervision of rheumatologists, but may be provided by other care providers.
In the 2007 guidelines, this important statement was included as a Point 3 marker. It was considered that "good clinical practice" and "high level of training" were sufficient opinion that was entirely expert. The panel of experts was unanimous that the statement is so universal that it represents a fundamental principle rather than a recommendation. To establish a definitive diagnosis in patients with early arthritis, the group suggested that the minimum diagnostic procedures should include a thorough medical history and clinical examination, considering the various possible causes of inflammatory arthritis. After excluding other causes of joint swelling and pain (eg, septic arthritis, trauma, arthrosis, gout), particular attention should be given to age, geographic area and travel history, number and nature of joints involved, axial/enthesal involvement, and extra-articular manifestations (eg, eye , skin, genitourinary and gastrointestinal symptoms), including recent infections. Minimum laboratory testing panel was proposed in the 2007 guidelines and should include testing for C-reactive protein (CRP)/erythrocyte sedimentation rate (ESR), complete blood cell count, transaminase levels, renal function and urinalysis, rheumatoid factor (RF), anticitrullated anticitrullinated peptide antibodies (ACPA) and antinuclear antibodies . In addition, the diagnostic procedure may be enhanced by microbiological and/or serological tests (reactive arthritis, synovial fluid microbial culture, Lyme disease, parvovirus infection, hepatitis B or C), uric acid testing, synovial fluid analysis (cells and polarized light microscopy, if this is necessary), chest and joint radiographs, but depends on the clinical situation and country.
2016 update of EULAR recommendations for the management of early arthritis: final recommendations based on evidence and expert opinion
1. Patients who develop arthritis (any swelling associated with pain or stiffness) should be referred to a rheumatologist within 6 weeks of symptom onset
2. Clinical examination is the method of choice to detect arthritis, which can be confirmed by ultrasonography
3. If a definite diagnosis cannot be made and the patient has early undifferentiated arthritis, risk factors for long-term and/or erosive disease, including the number of swollen joints, acute phase proteins, rheumatoid factor, ACPA and imaging findings, should be considered when making management decisions
4. Patients at risk of persistent arthritis should be started on DMARDs as early as possible (ideally within 3 months), even if they do not meet classification criteria for inflammatory rheumatic diseases
5. Among DMARDs, methotrexate is considered the gold standard**, the anchor drug*** and, unless contraindicated, should be the first-line treatment in patients at risk for chronic disease
* Anchor (from German Anker - anchor) is a fastener that is fixed in various ways to the load-bearing base and holds any structure. An anchor is a fastener. A bolt that has a hex head and expands into blades at the other end when the head is rotated.
***English term - anchor drug
Designed for powerful fastening into concrete or brick walls, inserted into a drilled hole that can withstand heavy weight loads. When the hex head rotates, the petals diverge and jam the anchor in the hole to death.
6.NSAIDs are effective symptomatic therapy, but should be used at the minimum effective dose, for the shortest possible time, after assessing the risks of the gastrointestinal tract, kidneys and cardiovascular system
7. Systemic glucocorticoids reduce pain, swelling and structural progression, but given their cumulative side effects, they should be used in the smallest dose as a temporary (<6 months) adjuvant treatment. To relieve local symptoms of inflammation, intra-articular glucocorticoid injections should be used.
8.The primary goal of DMARD treatment is to achieve clinical remission and regular monitoring of disease activity, adverse events, and comorbidities should guide decisions about selection and changes in treatment strategy to achieve this goal
9. Monitoring of disease activity should include counts of tender and swollen joints, joint patient and physician assessments, ESR and CRP, usually through the use of combined monitoring methods. Arthritis activity should be assessed 1 month to 3 months before treatment goals are achieved. Radiographic monitoring and patient diaries of treatment outcomes, such as functional assessments, can be used to complement monitoring of disease activity
10.Non-pharmacological interventions, such as dynamic exercises and occupational therapy, should be considered as an adjunct to treatment in patients with early arthritis
11. In patients with early arthritis, smoking, dental care, weight control, vaccination status, and treatment of concomitant diseases should be a general part of patient management
12.Information for patients about the disease, its results (including concomitant diseases) and its treatment is important. Curriculums aimed at coping with pain, disability, maintenance of work capacity and social participation can be used to support intervention
ACPA, anticitrullinated antibody peptide; CRP, C reactive protein; DMARD, Disease-modifying antirheumatic drugs; ESR, erythrocyte sedimentation; EULAR, European League Against Rheumatism; NSAIDs, non-steroidal anti-inflammatory drugs .
The Expert Committee's deliberations resulted in 12 recommendations (Box 1). Compared to 2007, previous recommendation 3 was converted to overriding principle C, while a recommendation for prevention (#11) was added. In addition, an amendment has been made to the numbering to better ensure logical consistency (rather than for reasons of priority). Table 1 shows the levels of evidence and assessment of the following recommendations, based on the Oxford levels of evidence assessment, as well as the level of agreement after anonymous voting by the Expert Committee.
Table 1 Figure 1 Algorithms based on the 2016 update of the European League Against Rheumatism recommendations for management of early arthritis. (A) Diagnosis and prognosis. (B) Treatment and strategy. *Combination with glucocorticoids preferred. †Low disease activity could be an alternative target in rare occasions. ‡Should also include weight loss, smoking cessation, dental care and vaccination. ACPA, anticitrullinated peptide antibodies; DMARD, disease-modifying antirheumatic drug; NSAID, non-steroidal anti-inflammatory drug, RF, rheumatoid factor.
This recommendation is virtually identical to its 2007 counterpart, but there are subtle changes in wording. Since 2005, two studies have confirmed that patients with inflammatory arthritis in general, and those with suspected RA in particular, should be referred to rheumatologists as early as possible. Delay in transmission is one of the most important reasons for late diagnosis and late initiation of effective treatment. Patients with early arthritis referred to a specialist within 3 months show better results in terms of drug-free remission, radiographic damage and (less need for orthopedic surgery) than those with late presentation. It is also fully compliant with the standards of care developed for patients with RA and the quality indicators set by European expert committees. Based on these data, as well as the clinical experience of the Committee members, it was recommended that diagnosis and initiation of treatment, as with a rheumatologist, should be made within a relatively short period of time after the onset of complaints, which justifies the wording “within 6 weeks” in this recommendation.
Swelling not due to trauma or joint deformity suggests early inflammatory arthritis, especially if associated with pain and morning stiffness >30 min. Several questionnaires assessing swelling, pain, and stiffness have been developed to assist in the detection of early arthritis. These questionnaires have good sensitivity (86–90%) and specificity (90%), but have only been tested in small patient samples and lack validation in an independent cohort validation. The Committee was of the view that an appropriately validated tool for general practitioners to properly diagnose and refer patients with early-onset arthritis is currently lacking. The strength of this recommendation was considered "good" (category B) (Table 1).
The expert committee unanimously appreciated the key role of clinical examination. Clinical examination is still the cornerstone of detection of synovitis. Perception does not exclude that shape images may be more sensitive in detecting synovitis. US, including power Doppler techniques, can suggest synovitis, showing thickening of the synovial membrane, bursa and/or tendon sheaths with increased blood supply. Several controlled studies have suggested greater sensitivity than clinical examination in detecting synovitis of the knee and joints. The US "EULAR recommendations for the use of joint imaging in the clinical management of rheumatoid arthritis" were assessed in detail. The Expert Committee did not recommend a more prominent role in the detection of synovitis, as it was widely felt that the potential decrease in specificity and lack of knowledge about the long-term consequences of positivity in individual patients did not currently justify a more prominent role for use in the United States. In addition, language specifically related to the Doppler role was removed because the Panel believes that the Doppler capability should be part of every joint review in any case.
MRI has also been suggested to be more sensitive than clinical examination in the early detection of synovitis, but may suffer from a lack of specificity, as has been suggested by the prevalence of MRI abnormalities in the normal population. In contrast to the US, which is now a common tool in many rheumatologist practices, long scan times, limited access and relatively high costs limit the widespread use of MRI. Therefore, the Expert Committee believes that MRI should be offered only in very complex cases or in patients with specific forms of arthritis, and that further research is needed to better determine the place of this imaging mechanism in the diagnosis of patients with early arthritis. MRI was part of the 2007 guidelines but has been removed from the current set.
This recommendation has been slightly rephrased because the Panel wished to emphasize that early undifferentiated arthritis should be clearly distinguished from early RA. Additionally, “imaging” was used instead of “radiographic” to show that imaging conditions other than simple radiographs can provide prognostic information. For patients with early arthritis, after ruling out specific forms of arthritis, the working diagnosis is often undifferentiated arthritis. The next step in the diagnostic procedure is to assess the risk of persistent and/or erosive arthritis, usually meeting the definition of RA, in a particular patient. This set is now considered an important guide for optimal therapeutic strategy.
Since 2007, many observational studies have assessed the prognostic value of laboratory and imaging studies in early arthritis. The most prognostic factors were analyzed in a multivariate manner in these studies to test their independent contribution. Typically, the dependent variables tested were persistence, erosiveness, or radiographic progression.
In most studies of RF and ACPA, positivity and levels of ACPA and RF have shown some predictive value for the development of persistent and erosive arthritis. This observation was clearly emphasized by the EULAR and ACR, with ACPAs, in addition to RF, receiving important weight in the 2010 ACR/EULAR classification criteria for RA. In addition, a number of recent studies support the independent association of ACPAs with the diagnosis of RA, as well as radiographic progression in patients with early arthritis. The significance of RF is similar to ACPAs in the 2010 ACR/EULAR classification criteria for RA, although recent publications arising from early arthritis cohorts and observational studies indicate that the prognostic and diagnostic value of RF is lower compared to ACPAs, but RF has a strong association with disease activity regardless of the presence of ACPA. The combination of RF and ACPAs does not provide additional value to RF or ACPAs alone. In addition to ACPA, the number of swollen joints and the levels of CRP and ESR are independent factors.
Early erosion of typical RA is still a major prognostic factor in the onset of arthritis and automatically leads to the classification of RA. Synovitis and erosion detected by MRI or US (ultrasound) may predict further progression at the onset of arthritis, but less positivity has been reported. MRI has found bone marrow edema and osteitis to be independent predictors of radiographic progression in early RA, but data are limited in early arthritis. Finally, two recent studies have shown that flexor and extensor tendovaginitis on US or MRI may be a specific, although not very sensitive, marker for RA classification.
Several combinations of diagnostic markers have been evaluated, but none have been formally validated. Additionally, multibiomarker tests have been proposed to assess disease activity, prognosis, and response to therapy, but current evidence is inconclusive and further research is warranted. Finally, the replacement MRI for clinical examination in the 2010 ACR/EULAR criteria was reported to increase sensitivity but decrease specificity for diagnosing RA. MRI is therefore of limited value in making the diagnosis of RA and is not recommended as a routine procedure.
This recommendation has been slightly modified and re-emphasizes the Committee's consensus that early treatment is critical in the treatment of patients with early chronic arthritis, such as early RA, early PsA, or people at risk of developing persistent and erosive disease. The wording "RA" is not used in this statement, but the implication is that persistent and/or erosive disease is effectively synonymous with RA (see previous point) and justifies early initiation with DMARDs. A new element is a maximum delay of 3 months after symptom onset before starting the first DMARD. The Expert Committee was of the opinion that this time frame represents a “window of opportunity” to ensure optimal outcome in at-risk patients. Eight recent studies supported early treatment. Four studies showed that administration of DMARDs within 3 months of symptom onset resulted in better outcome (remission, response to treatment, Health Assessment Questionnaire Disability Assessment, or radiographic progression). Additionally, duration of illness before DMARD initiation was the most important determinant of DMARD response in another study. This statement may raise questions about the best definition of “early RA.” A duration of 3 months after symptom onset may be the longest acceptable delay in starting the first DMARD. However, the maximum delay remains difficult to meet in daily practice, while most recent “early RA” cohorts allow a delay of 6 months from symptom onset (joint swelling is common) for inclusion. A delay of no more than 6 months was also suggested in recent RA guidelines. A delay of more than 1 year from symptoms should not be considered “as early” ever again.
Designed for powerful fastening into concrete or brick walls, inserted into a drilled hole that can withstand heavy weight loads. When the hex head rotates, the petals diverge and jam the anchor in the hole to death.
This recommendation (previously #9) remains almost unchanged. Previous SLRs support the clinical and structural efficacy as well as safety profile of MTX. An important argument for supporting MTX as an anchor drug in first-line treatment in patients at risk of persistent arthritis (eg, at risk of RA) is its good efficacy in early RA and its “practicality”, both as monotherapy and in combination with glucocorticoids (GC). , other csDMARDs and bDMARDs. Recent trials in early DMARD-naive RA patients evaluated MTX monotherapy versus csDMARDs, in combination with different dosages and courses of GC administration. Verschueren et al recently reported remission after 16 weeks in high-risk patients with early RA receiving MTX monotherapy, MTX plus sulfasalazine (SSZ), or MTX plus leflunomide (LEF), all combined with high-dose prednisolone, as bridge therapy . In another study, MTX plus temporary high-dose prednisone was no less effective than MTX plus CVD plus temporary high-dose prednisone after 26 weeks. The Treatment in Rotterdam Early Arthritis Cohort (tREACH) noted the short-term superiority of MTX in combination with CVD, Hydroxychloroquine and GC compared to MTX and GC, but did not see this superiority in all aspects, which is not clinically significant and does not ultimately persist. after 1 year. Treatment of early aggressive rheumatoid arthritis (study) trial does not support the benefit of an intensive csDMARDs combination regimen over MTX monotherapy. In the absence of clear data for the superiority of a combination regimen of csDMARDs and guided by the trend toward lower tolerability for the csDMARD combination, the Committee was of the opinion that the first treatment strategy should be MTX monotherapy or without short-term high-dose GC as overcoming therapy for most patients. In this regard, dose optimization is an important aspect of the first-line DMARD strategy, as previously reported (MTX should be rapidly titrated to 20–30 mg per week, depending on clinical response and tolerability; parenteral administration should be considered in case of inadequate clinical response or intolerance).
The superiority of bDMARDs plus MTX over MTX monotherapy has been demonstrated in numerous randomized controlled trials (RCTs) and has been confirmed by eight recent studies in the ongoing SLR. In addition, two targeted synthetic DMARDs have recently demonstrated superiority to MTX as monotherapy in patients with early RA. However, because the benefit-to-risk ratio of these biologic and targeted synthetic DMARDs is not convincingly favorable in patients with early disease, because in any case tight monitoring is part of the current treatment strategy to identify individuals requiring the addition of biologics, and because of their high cost, the Expert Committee considered their use as a first treatment strategy inappropriate except in rare situations.
There are no recent RCTs comparing other csDMARDs with MTX. The clinical efficacy of LEF, and to a lesser extent CVD, is similar to MTX in established and recent RA. LEF is as effective as MTX in slowing radiographic damage, and its therapeutic tolerability is similar to MTX. In contrast, CVD may be worse than LEF and MTX in the long term. Although formal evidence prioritizing MTX over other csDMARDs as the first DMARD used in early arthritis and/or onset RA is lacking, the Expert Committee recommended MTX as the first choice of treatment (unless contraindicated) in patients at risk for persistent disease. LEF and (to a lesser extent) CVD are seen as better alternatives. In addition, CVD is considered safe during pregnancy, unlike MTX and Lef. Finally, the Committee is of the view that antimalarials, which have shown less clinical efficacy and may not delay radiographic progression in patients with RA but may have beneficial metabolic effects, may be considered as a partner in combination therapy or DMARD monotherapy in patients with mild disease. and concomitant diseases or persistent arthritis other than RA.
SLR did not provide new evidence for NSAIDs in patients with early arthritis. The Expert Committee believes that symptomatic therapy with NSAIDs remains of value in patients with early arthritis, but only after careful evaluation of gastrointestinal, renal, and cardiovascular contraindications. In addition to previous point #7 on NSAIDs, the group is now reinforcing the need to adhere to the US Food and Drug Administration and European Medicines guidelines, which recommend shortest treatment duration, minimum effective dose, and contraindications for at-risk patients (http://www. fda.gov; http://www.ema.europa.eu).
The role of GC in the management of early arthritis is being actively discussed by an expert committee. This discussion was based on expert opinion and new information received from SLR. Recently, one meta-analysis of 14 RCTs in patients with RA and 2 RCTs in patients with “early RA” confirmed that systemic GC improves clinical and radiographic outcomes. It is preferable that therapy with systemic GC be temporary due to the risk of side effects, including weight gain, hypertension, diabetes, cataracts and osteoporosis, which warrant careful monitoring and appropriate warnings. New evidence emerging from registries, observational studies, and expansion of RCTs also suggests an increased risk of severe infections, cardiovascular events, and mortality. In addition, there is evidence that intra-articular steroids may be an effective adjunct to DMARDs in relieving joint symptoms in patients with early arthritis and may improve disease activity for up to 24 months.
The Committee would reword this point (No. 8 in previous recommendations) to emphasize the effectiveness of systemic GC in relieving symptoms and disease progression, but also to highlight the risks of cumulative side effects in the medium to long term. The Committee is of the opinion that GC can only be justified if used at the lowest possible total dose, for the shortest possible duration, and solely as an adjunct (or bridge) to csDMARDs therapy. GC monotherapy may mask disease activity before diagnosis is established and should be avoided in patients with early arthritis in order to expedite correct diagnosis and ensure adequate prognosis and early initiation of DMARD treatment. Despite heated debate, this recommendation was finally approved by 95% of members and received a high level of agreement (mean 9.00±1.28) with anonymous voting. The formulation of “low dose” and the optimal regimen (low daily dose or high dose tapered or parenteral pulse) for early arthritis are under debate and will be mentioned in studies (Box 2).
Research program for the management of early arthritis
Diagnosis and prognosis
Treatment and results
csDMARDs, conventional synthetic Disease-Modifying Anti-Rheumatic Drugs; DMARD, Disease-modifying antirheumatic drugs.
The 2007 recommendations for patients with early-onset arthritis were among the first guidelines to highlight clinical remission as a primary goal in the care of these patients. Over the past 10 years, accumulating evidence supports this as a primary treatment goal for RA and other inflammatory arthritis. The Expert Committee decided to keep the wording of previous recommendation No. 10 unchanged. Several new studies have confirmed that achieving clinical remission earlier is a possible outcome in improved clinical outcomes and quality of life and helps prevent further structural damage, functional disability and loss of work in patients with early arthritis and early RA. Which criteria, especially for remission, should be used in practice remains unclear. Activity scales (Disease Activity Score (DAS), DAS28, Clinical Disease Activity Index, Simplified Disease Activity Index (SDAI)) should be used, and probably the most stringent ACR-EULAR remission criteria (Boolean or SDAI). An interesting definition for daily practice is “the absence of signs and symptoms of significant inflammatory disease activity. Recent evidence has suggested that remission leads to a better outcome than low disease activity ( LDA ) , and the Committee opined that clinical remission by the ACR-EULAR Boolean or index-based definition is the goal for every patient with early arthritis. LDA status may be an acceptable alternative goal only in cases where remission is not considered feasible. In this regard, factors such as comorbidities, age or adverse events should be considered and may determine the goal of the desired treatment, which will serve as the basis for the shared decision-making process with the patient.
The Expert Committee also discussed whether imaging (meaning X-ray, MRI, US) **** of remission should be included in the goal, as has been suggested by some recent recommendations. Studies have shown that ongoing inflammation, as detected by US and to a lesser extent MRI, in patients with clinical remission can predict structural progression. However, its significance and its clinical utility are questionable and associated with significant costs and thus a potential waste of society's resources; The SLRs did not provide any new information. Therefore, the Expert Committee suggested that the value of remission imaging should be part of the research agenda.
Finally, the Committee believes that disease activity should be closely monitored to allow for timely changes in DMARD therapy when necessary. The benefits of a targeted treatment approach have now been convincingly demonstrated in patients with RA and PsA and there is no reason to believe that the situation is different for early arthritis.
Radiographic monitoring and patient diaries as functional assessments can be used to complement monitoring of disease activity.
Monitoring the disease activity of each patient with active arthritis is now considered of particular importance in the therapeutic strategy to ensure a good outcome, as evidenced by all the most recent recommendations. Monitoring of disease activity should be as frequent as long as disease activity persists, usually every 1–3 months, but then less frequently (eg, every 6–12 months) once the treatment target has been achieved.
However, three changes to this paragraph (previously No. 12) were proposed. First, comprehensive assessment has been recommended as the method of choice for monitoring disease activity; Second, the specific time frame for monitoring structural damage was intentionally omitted and third, patient diary data exceeded the results of functional assessments.
A connection has been established between the count of swollen joints and the progression of joint damage. In addition, many trials support the use of tight monitoring of disease activity, through activity scores that include counts of joint changes. Although it is difficult to formally study, the Expert Committee opined that monitoring the occurrence of radiographic progression is useful given one of the key goals of management of early arthritis: preventing joint destruction. Determining the optimal window for monitoring progression was added as a research agenda item (Box 2).
Finally, patient-reported outcomes such as quality of life, fatigue, and physical function are key to outcome assessment and are considered by the Committee to be part of disease monitoring.
This recommendation remains virtually unchanged. The effectiveness of non-drug therapy has not been studied in early arthritis and can only be drawn from the results of several RCTs in established RA. Hydrotherapy in patients with RA has been evaluated in some studies, but with insufficient evidence to support a strong recommendation; Consequently, hydrotherapy was not included in the current guidelines, but may be considered at the individual patient level. Previous RCTs have shown that joint specific dynamic exercise can improve strength and physical function in RA, but the current SLR identified some conflicting results on disease activity. Occupational therapy can improve functional management and self-management, but does not have a positive effect on disease activity; No recent studies were found.
Finally, psychological counseling may be considered for individual patients, but trials of the effectiveness of psychological interventions are lacking and the Committee did not include them in the statement. In addition, no relevant SLR studies have been identified that assessed the effectiveness of the diet.
Because dynamic exercise, occupational therapy and, to a lesser extent, hydrotherapy have been associated with symptomatic relief in patients with established RA, the Expert Committee decided to include them as adjuvant therapy to pharmaceutical therapy in patients with early arthritis.
This recommendation is new and is mainly based on expert opinion. The Expert Committee believes that over the past decade, evidence has accumulated that emphasizes the importance of managing comorbidities (eg, cardiovascular disease, metabolic conditions (eg, hyperlipidemia, diabetes mellitus), pulmonary disease, infections, malignancies, osteoporosis, and depression) in context of management of early arthritis. Comorbidities may affect life expectancy and outcomes (physical function, quality of life) regardless of disease activity in patients with inflammatory arthritis. In addition, concomitant diseases may affect the effectiveness and safety of antirheumatic therapy. Obesity and smoking may affect the response to treatment for inflammatory arthritis. Prevention is considered the key in the management of chronic inflammatory rheumatic diseases, but optimal management of comorbidities has not yet been developed. Smoking is the most modifiable risk factor in the development of RA and spondyloarthritis. In addition, tobacco consumption was associated with the presence of extra-articular manifestations such as rheumatoid nodules, as well as serum RF and ACPAs. Although smoking is not associated with persistence of disease activity or progression of RA, it may influence the development of spondyloarthritis.
RA is associated with periodontal disease, although this relationship still remains unclear. The microbiome may play a role in chronic arthritis risk and progression, and Porphyromonas amoeba infection may contribute to aberrant circulation and local impaired tolerance to citrulated peptides. Potentially beneficial contributions of oral health care have been made to research agendas.
Although the available evidence does not demonstrate that risk factor modification is beneficial for patients, the modifiable risk factors identified in the SLR are so general, the Committee unanimously believes that recommendations aimed at abolishing their potential impact on arthritis (and overall health) would not be harmful patients and may provide certain benefits.
In addition, the Expert Committee noted that a small number of patients with chronic arthritis are currently receiving vaccinations and that this should be specifically mentioned.
This recommendation was very similar to the previous No. 6. Obviously, full transparency regarding the disease and its treatment should be an integral part of the management of any chronic disease and represents the basis of the overriding principle. Other physicians share the importance of providing information. Research has shown that treatment adherence depends on the quality of information exchange and the quality of interaction between the patient and health care professionals, including rheumatologists.
EULAR recently recommended that "people with inflammatory arthritis should have access to and offer education to patients throughout the course of their illness, including, at a minimum, on diagnosis, drug treatment changes and, if appropriate, the patient's physical or psychological condition." The content and delivery of patient education should be individualized, with individual and group sessions representing a variety of delivery approaches. Priorities for uniform educational interventions, since all intervention trials have only short-term benefits and are subject to cross-national and cultural variations. Improving quality of life is a major goal for patients, and the Committee suggested adding “social participation” as one of the goals of these education programs. The Expert Committee also believes that patients should be aware that comorbidities may affect the outcome and treatment of inflammatory arthritis, and that their screening and management should be part of the global management of early arthritis.
Updated EULAR recommendations for the management of early arthritis continue the 2014 EULAR standard operating procedures. The committee proposed an important revision of the elements, but it is clear that most of the core recommendations remained intact. These updated guidelines for the management of early arthritis contain 3 general principles, 12 recommendations and 2 algorithms that bring together all the latest developments in the management of early arthritis. The definition of the term "management" has been consistent and includes all spectrums of early arthritis management, including presentation, diagnosis, prognosis, classification, information, education, nonpharmacologic interventions, and pharmacologic treatments and disease monitoring. The term "early arthritis" has been limited to "early inflammatory arthritis" and primarily, but not exclusively, focused on the risk of chronic arthritis.
The expert committee had to face the limitation that most of the published data on treatment and strategies on which they could base their recommendations were participating studies in patients with early RA or established RA, rather than specific studies of early arthritis. Despite this limitation, the Committee considered most of the evidence for early RA to be sufficiently robust and relevant to extrapolate "early arthritis is likely to become persistent." The scope differs from the EULAR recommendations for the management of RA, which focused on the use of DMARDs in early and established disease. However, there is overlap regarding first-line therapy for early arthritis at risk of persistence (Figure 1) and early RA (DMARD naïve and usually <6 months of disease duration). Unsurprisingly, the two sets of recommendations are very similar on these specific issues.
These recommendations have important advantages, including the composition of the Expert Committee, consisting of 20 rheumatologists, including 2 research fellows from 12 European countries and the new addition of 1 specialist and 2 patient representatives. The committee selected the grade level of evidence presented by each study, which was based on the study methodology, and took this rating into account when discussing the content and strength of the recommendations. An important consideration in the discussions was whether the type of study always determined the content of the research question, which was based on the literature search. The recommendations were based on the most recent evidence and expert opinion. For example, the Expert Committee believes that the evidence supports comorbidities as a possible outcome of arthritis, as well as treatment effectiveness and safety, and should be considered in the management of all early cases of arthritis. Despite the sparse evidence, the expert committee would also like to point out that smoking cessation and dental care may be offered to patients with early arthritis, and that both patients and health care workers should be made aware of the importance of improving vaccination coverage. In this regard, a new recommendation on prevention has been added (item no. 11). Of note, the level of agreement among experts was high for each element (means 9.0 – 9.9), which supports the appropriateness and validity of the recommendations.
In light of the current literature and despite important recent advances, the Committee believes that continued development of new tools is necessary for early and accurate diagnosis and prognosis, including new biomarkers, a better understanding of the value of US and MRI, and the establishment of predictive algorithms for long-term outcome (Box 2). Finally, the Expert Committee believes that further research is needed on the comparative effectiveness and cost-effectiveness of various policy mechanisms in the onset of arthritis, including the effectiveness of non-pharmacological interventions.
Although these recommendations are not deliberately called 'guidelines', they reflect the strong views of many European experts, including patient representatives. They should provide rheumatologists, general practitioners, medical students, healthcare professionals, health authorities and patients with a practical approach to the management of early arthritis, although each clinician must select the most appropriate management strategy for each individual patient. To this end, it is expected that the recommendations will be widely disseminated and discussed within the community of rheumatologists and other health care professionals caring for patients with early arthritis, and that they will help improve the level of care for patients with arthritis across various health care systems. Obviously these recommendations will likely need to be amended after about 5 years to incorporate new scientific evidence.