Note from the National Guideline Clearinghouse: This guideline references a drug(s) for which important revised regulatory information has been released:
On April 7, 2005, after concluding that the overall risk versus benefit profile is unfavorable, the U.S. Food and Drug Administration (FDA) requested that Pfizer, Inc voluntarily withdraw Bextra (valdecoxib) from the market. The FDA also asked manufacturers of all marketed prescription nonsteroidal anti-inflammatory drugs (NSAIDs), including Celebrex (celecoxib), a COX-2 selective NSAID, to revise the labeling (package insert) for their products to include a boxed warning and a Medication Guide. Finally, FDA asked manufacturers of non-prescription (over the counter [OTC]) NSAIDs to revise their labeling to include more specific information about the potential gastrointestinal (GI) and cardiovascular (CV) risks, and information to assist consumers in the safe use of the drug. See the FDA Web site for more information.
Subsequently, on June 15, 2005, the FDA requested that sponsors of all non-steroidal anti-inflammatory drugs (NSAID) make labeling changes to their products. FDA recommended proposed labeling for both the prescription and over-the-counter (OTC) NSAIDs and a medication guide for the entire class of prescription products. All sponsors of marketed prescription NSAIDs, including Celebrex (celecoxib), a COX-2 selective NSAID, have been asked to revise the labeling (package insert) for their products to include a boxed warning, highlighting the potential for increased risk of cardiovascular (CV) events and the well described, serious, potential life-threatening gastrointestinal (GI) bleeding associated with their use. FDA regulation 21CFR 208 requires a Medication Guide to be provided with each prescription that is dispensed for products that FDA determines pose a serious and significant public health concern. See the FDA Web site for more information.
These recommendations are presented in abbreviated form. Readers should refer to the text of the guideline document for a detailed discussion of each of the following topics.
Definitions for the type of evidence (1-7) and the strength and consistency of evidence grades evidence (A, B, C) are provided at the end of the Major Recommendations field.
Diagnosing Rheumatic Arthritis
Rheumatoid arthritis (RA) should be suspected in patients over 16 years of age who have joint inflammation or effusion of more than 6 weeks duration in three or more joints, preferably of the hands and feet. To date, the only universally accepted and used diagnostic criteria for RA are those proposed by the American College of Rheumatology (ACR) for classification of the disease.
According to the ACR, the diagnosis of RA requires confirmation of at least four of the following criteria:
- Morning stiffness lasting at least one hour before maximal improvement, for at least 6 consecutive weeks.
- Soft tissue swelling or effusion, observed by a physician, in at least three of the following joint areas (right or left): proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, elbow, knee, ankle, or metatarsophalangeal (MTP) joints, for at least 6 consecutive weeks.
- Swelling or effusion, observed by a physician, in the proximal interphalangeal, metacarpophalangeal, or wrist joints, for at least 6 consecutive weeks.
- Symmetrical (right and left sides) swelling or fluid in the joints mentioned in point 2, observed by a physician, for at least 6 consecutive weeks.
- Subcutaneous nodules over bony prominences or extensor surfaces, or in juxta-articular regions, observed by a physician.
- Demonstration of serum rheumatoid factor (RF) detected by any method that has been positive in less than 5% of control subjects.
- Radiographic evidence in the hands or wrists of articular erosions or osteopenia in or around the affected joints.
Initial Evaluation
Patients with RA should be evaluated and treated by physicians who are familiar with the clinical management and treatment of the disease.
The initial evaluation of a patient with RA should include a clinical history and physical examination.
The clinical history should include background information that is important for RA diagnosis and treatment, including previous diseases, life style, gynecological history, and occupation. If the patient has been diagnosed with RA, the history should describe the clinical characteristics of the disease obtained by patient interview and by reviewing reports and other documents provided by the patient such as radiographs and laboratory tests. An understanding of how RA has evolved requires knowledge of all types of previous and concurrent treatments, especially with analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs (DMARDs), including the dosage, duration, reasons for withdrawal, tolerance, and side effects.
In the physical examination, note should be taken of the presence of pain, joint inflammation, deformities, and subcutaneous nodules.
The evaluation and monitoring of RA should be based on a systematic evaluation of a minimum set of parameters including joint pain and inflammation, the patient’s global assessment of pain, global assessment of disease, functional disability, acute phase reactants, and radiologic evidence of damage.
Validated methods should be used to assess the number of painful joints and the number of swollen joints. Although the clinician will consider different factors in the choice of which index to use, this guideline recommends the ACR count.
The articular indices assess the degree of pain and swelling by counting the number of painful joints and the number of swollen joints. Different methods have been described, varying in the number of joints evaluated, although only four are in widespread use: the ACR count, Ritchie index, 44-joint index, and 28-joint index.
ACR count. The ACR count is considered to be the most complete index and is the US standard. It includes an evaluation of tenderness in 68 joints and swelling in 66 joints (excluding both hips). The following joints are assessed: distal interphalangeal, proximal interphalangeal, metacarpophalangeal, wrist, elbow, shoulder, acromioclavicular, sternoclavicular, temporomandibular, hip (only for pain), knee, ankle, subtalar, metatarsophalangeal, and proximal interphalangeal joints.
The subjective experience of pain should be assessed by the patient. It is recommended that pain be measured using a horizontal visual analog scale, 10 cm in length, divided by vertical marks into ten equal 1-cm segments. The measurements should be accompanied by numeric descriptors from 0 to 10, with indicators at each end showing no pain (0) and worst pain (10).
A global assessment of disease should be made from the medical point of view and another one from the patient’s point of view. For this measurement, the use of a 10 cm horizontal visual analog scale is recommended, with vertical marks dividing it into 10 equal 1-cm segments. The measurements should be accompanied by numeric descriptors from 0 to 10, indicating at each end "very good" (0) and "very poor" (10).
Global disease assessments by both the physician and the patient are useful because their evaluations may be quite different. The global assessment is very sensitive to clinical changes.
Self-perceived functional disability attributed to the disease should be evaluated using specific, previously validated questionnaires such as the Health Assessment Questionnaire (HAQ).
There are various ways to estimate functional capacity based on joint mobility or the ability to perform certain tasks as evaluated by an observer. The most widespread methods currently used consist of specific questionnaires for rheumatic disease such as the HAQ or its abbreviated form, the Modified Health Assessment Questionnaire (MHAQ), or the Arthritis Impact Measurement Scale (AIMS). They are based on the patient’s own opinion about his or her disease. These questionnaires are standardized instruments of proven validity and reliability. They evaluate those health dimensions that are most affected by RA, particularly disability, especially in relation to physical function, and pain.
This guideline recommends the use of the HAQ, a 19-item self-administered questionnaire that evaluates self-perceived physical disability to perform different activities of daily living grouped into eight areas: dressing and grooming, rising, eating, walking, hygiene, reaching, gripping, and other activities.
Laboratory tests should include the acute phase reactants (APRs) erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). These two APRs are good indicators of the inflammatory activity of the disease.
Laboratory tests should consist of a complete blood count, acute phase reactants (ESR, CRP), rheumatoid factor (RF), liver function (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT], gamma-glutamyl-transferase [GGT], alkaline phosphate, albumin), kidney function (creatinine), calcium, and urinalysis. The presence of hepatitis B and C virus should be evaluated (in relation to the hepatotoxicity of some of the drugs used in treatment).
These basic tests will facilitate RA monitoring and early detection of disease complications and side effects of treatment. Whether to include other, complementary tests is left to the judgment of the individual physician.
Radiographs of the hands, feet, and chest are recommended at the initial evaluation. Radiographs of the feet and hands should be repeated annually for the first 3 years of disease evolution, and thereafter as deemed appropriate.
The radiographs should be examined for the presence of bony erosions, which are more frequent at disease onset. About 70% of patients have erosions of the hands or feet by the end of the first 2 or 3 years. Their presence and the speed of onset are associated with poorer outcome. Radiographs of both hands and feet are justified by the fact that asymmetrical erosions (right or left) may appear, and by the observation that in the first 2-3 years of the disease, erosions appear only on the feet, without clinical symptoms, in up to 23-36% of patients.
A chest X-ray is recommended for initial evaluation and to identify the appearance of possible problems during the course of the disease and its treatment.
The use of a composite index of disease activity, summarizing various parameters in a single indicator, is a useful and valid procedure in assessing disease activity. As calculating such an index can be time consuming, this guideline leaves its use to the judgment of the individual rheumatologist. If one of these indices is used, however, this guideline recommends the Disease Activity Score (DAS), in any of its versions.
These indices differ in the number of parameters included as well as in the methods used for their calculation. Their advantages in comparison to conventional evaluation using single parameters are that they avoid duplicate measurements and are more sensitive to change. Their disadvantages are a certain degree of complexity in the calculations, difficulty of interpretation, and some problems related with how they are constructed.
The DAS includes the Ritchie index (see description in the original guideline document), the number of swollen joints out of 44 joints (NSJ44), ESR, and the patient’s global assessment of disease (PGA) on a visual analog scale (0 cm "very good" – 10 cm "very poor"). The DAS is calculated using the formula provided in the original guideline.
There is a modified DAS based on counts of the number of painful joints (NPJ28) and the number of swollen joints (NSJ28) out of 28 joints (refer to the original guideline document for the formula). The score for the complete DAS and the DAS28 can range from 0 to 10.
The initial and subsequent evaluation of patients with RA should include a continual estimate of disease prognosis.
The outcome of RA varies considerably among patients. Some treatment strategies, more aggressive and therefore more toxic, improve RA outcome when used early in patients with a high risk of developing functional disability or structural damage and/or of mortality. Since most radiographic changes and loss of functional capacity occur in the first few years of evolution, the earlier a disease prognosis is formulated, the earlier it will be possible to make an informed decision on the most appropriate treatment strategy.
RA outcome can be estimated more accurately by combining various factors than by considering a single factor. The factors predictive of serious disease (functional disability, radiologic erosions, and mortality) can be classified as sociodemographic, disease-dependent, and treatment-dependent. The sociodemographic factors associated with poor outcome are female sex and low educational level. Among the disease-dependent factors associated with poor outcome are positive RF, more than 20 swollen joints at disease onset, elevated CRP, ESR greater than 60 mm in the first hour, elevated HAQ at the first visit, early involvement of large joints, rapid appearance of erosions (> 2/year), and the presence of extra-articular manifestations (rheumatoid nodules, vasculitis, scleritis, or others). The treatment factors associated with better outcome are early initiation of DMARD treatment and total time in treatment with DMARDs during the course of the disease.
Factors related with the patient’s psychological and social situation should be taken into account because they can affect the assessment of pain and development of disability.
Depression and anxiety are very frequent in RA from the time of disease onset due to the impact of confronting its diagnosis and evolution. Depression and anxiety are closely related with chronic pain and the development of disability. Some psychological characteristics of the patient (level of perceived helplessness, coping ability, level of self-management) play an important role as factors predictive of disability and health status. Patients who receive social support from family members, especially from spouses, have better outcomes and less disability.
A detailed evaluation should be made to rule out latent tuberculosis infection before beginning treatment with immunosuppressants, anti-tumor necrosis factor (TNF) agents, or corticosteroids. If latent tuberculosis infection is present, prophylactic treatment with isoniazide is recommended.
Classifying Rheumatic Arthritis
The classification of RA is based on the two characteristics that have the most influence on treatment decisions and outcome: the presence or absence of erosions and the number of swollen joints. This classification may be made more precise if other factors such as APR, HAQ, and RF are taken into account.
RA cannot be neatly classified into different categories. In this guideline, the classification of patients is based on two principles: first, classifying RA is useful for making treatment decisions and estimating patient outcome; second, the classification should help the physician in actual practice. In accordance with these two principles, RA is classified based on the two parameters that, in the panel’s opinion, have the most influence on treatment decision and outcome: the presence of erosions and the number of swollen joints. The use of two categories for the presence of erosions (yes/no) and two categories for the number of swollen joints (<6/>6), gives four types of RA. Further differentiation in the classification process by considering other factors such as APRs, HAQ, and RF results in 144 different patient types, from the most mild clinical presentation (no erosions, <6 swollen joints, normal APRs, HAQ<1, and negative RF) to the most severe (erosions present, >10 swollen joints, elevated APRs, HAQ>1, and high titers of positive RF). Each patient, according to the initial disease characteristics, should begin a specific treatment option (see chapter 4 of the original guideline document).
Two types of RA are excluded from this classification: "burnt-out" or end-stage RA and pseudopolymyalgic RA.
"Burnt-out" or end-stage RA is RA without inflammatory activity and with complete or practically complete destruction of the patient’s joints. It is characterized clinically by joint pain at rest or with minimal exertion, joint deformities, severe muscular atrophy, extreme functional disability, and radiographic evidence of major joint destruction (erosions, subluxations, and ankylosis). The evaluation should rule out the presence of the extra-articular complications or manifestations of RA that most frequently appear at this stage of the disease, for example, skin ulcers, vasculitis, or amyloidosis.
Pseudopolymyalgic RA is a disease that affects patients over 60 years of age and is characterized by the sudden onset of symptoms, mainly affecting the proximal joints (shoulders and hips) as well as the knees and carpal joints. It is accompanied by considerable morning stiffness, negative RF, and a marked increase in APRs. Erosions do not usually develop and the prognosis is generally good, with possible spontaneous remission of the disease in 6-24 months.
The differential diagnosis of pseudopolymyalgic RA is difficult since it is very similar to polymyalgia rheumatica. It is usually managed effectively with corticosteroids. If a satisfactory response is not obtained, it should be treated the same as RA, taking special considerations into account for elderly patients.
Medical Treatment of Rheumatoid Arthritis
Initial treatment of rheumatoid arthritis
In general, patients with RA should be treated with a DMARD as soon as the disease is diagnosed.
An attempt may be made to treat only with NSAIDs and/or corticosteroids for a maximum of 3 months, and only in patients who have not used these drugs during the 3 months before the disease was diagnosed, who have fewer than 6 swollen joints, no erosions, negative RF, and normal APRs.
All RA patients who remain symptomatic (with pain and swelling) despite treatment with DMARDs should be treated with steroidal or nonsteroidal anti-inflammatory agents and analgesics.
Because of its efficacy and toxicity profile, methotrexate is the recommended initial treatment in all patients who have not previously received DMARD treatment. Nevertheless, initial treatment with other drugs is also considered acceptable, in accordance with the clinical classification of disease shown in the accompanying table.
Simplified Clinical Classification of RA
| SIMPLIFIED CLINICAL CLASSIFICATION OF RA |
Recommended initial treatment, by order of preference (supporting evidence) |
| No erosions |
<6 swollen joints |
Methotrexate (1)
Sulphasalazine (2)
Chloroquine (3) |
| >6 swollen joints |
Methotrexate (1)
Injectable gold (4) |
| Erosions present |
<6 swollen joints |
Methotrexate (1) |
| >6 swollen joints |
Methotrexate (1)
Leflunomide (5)
Methotrexate + injectable gold (6) |
(1) Methotrexate is more efficacious than oral gold (A1 evidence) or azathioprine (A2 evidence). No significant differences have been found in the efficacy of methotrexate compared with etanercept, leflunomide, sulphasalazine (A1 evidence), injectable gold (A2 evidence), cyclosporin, or infliximab (B evidence).
(2) Sulphasalazine is more efficacious than hydroxychloroquine (A2 evidence), and no significant differences have been found in the efficacy of sulphasalazine compared with leflunomide, methotrexate (A1 evidence), oral or injectable gold, and D-penicillamine (B evidence).
(3) Chloroquine is not significantly different in efficacy from cyclosporin, oral gold (A2 evidence), azathioprine, injectable gold, and D-penicillamine (B evidence).
(4) Injectable gold is not significantly different in efficacy from oral gold (A1 evidence), cyclosporin and methotrexate (A2 evidence), or chloroquine, D-penicillamine and sulphasalazine (B evidence). It is less efficacious than azathioprine and cyclophosphamide (B evidence).
(5) Leflunomide (A1 evidence) shows no differences in efficacy as compared to methotrexate and sulphasalazine (A1 evidence).
(6) No clinical trials have evaluated the efficacy of treatment with methotrexate+injectable gold (C evidence).
Changes in treatment
Treatment failure or toxicity should be evaluated within a maximum of 3 months, and a change in treatment should be considered.
Whatever initial treatment is chosen, the patient should be closely monitored. If a satisfactory response is not obtained in 3 months or if serious drug-related toxicity develops, the treatment should be modified.
Changes in treatment due to toxicity or unsatisfactory response
If serious adverse effects appear, an alternative treatment should be substituted for the treatment of first choice. If the treatment shows no toxicity but the response is unsatisfactory even after using the maximum dose, an alternative treatment should be substituted for the treatment of first choice.
For patients in whom alternative treatments fail due to unsatisfactory response, toxicity, or other reasons, the use of any DMARD or DMARD combination of proven efficacy is recommended (see tables 4, 5 and 8 of the original guideline document); if these fail, experimental treatments may be tried.
Changes in treatment due to toxicity or unsatisfactory response should be made in accordance with the following tables.
Alternative treatment in case of severe toxicity of initial treatment
| SIMPLIFIED CLINICAL CLASSIFICATION OF RA |
First-choice treatment used |
Alternative treatment in case of toxicity, in order of preference (supporting evidence) |
| No erosions |
<6 swollen joints |
Methotrexate |
Leflunomide (1)
Injectable gold (2)
Sulphasalazine (4) |
| Sulphasalazine |
Methotrexate (3)
Injectable gold (2) |
| Chloroquine |
Methotrexate (3)
Injectable gold (2) |
| >6 swollen joints |
Methotrexate |
Leflunomide (1)
Injectable gold (2) |
| Injectable gold |
Methotrexate (3)
Leflunomide (1) |
| Erosions present |
<6 swollen joints |
Methotrexate |
Leflunomide (1)
Injectable gold (2)
Sulphasalazine (4) |
| >6 swollen joints |
Methotrexate |
Leflunomide (1)
Injectable gold (2)
Sulphasalazine (4) |
| Leflunomide |
Methotrexate (3)
Anti-TNF (5) |
| Methotrexate+injectable gold |
Leflunomide (1)
Anti-TNF (5) |
(1) Leflunomide (A1 evidence) shows no differences in efficacy as compared to methotrexate and sulphasalazine (A1 evidence).
(2) Injectable gold has not been shown to have significant differences in efficacy as compared to oral gold (A1 evidence), cyclosporin and methotrexate (A2 evidence), or chloroquine, D-penicillamine and sulphasalazine (B evidence). It is less efficacious than azathioprine and cyclophosphamide (B evidence).
(3) Methotrexate is more efficacious than oral gold (A1 evidence) or azathioprine (A2 evidence). No significant differences in the efficacy of methotrexate have been found in comparison with etanercept, leflunomide, sulphasalazine (A1 evidence), injectable gold (A2 evidence), cyclosporin, or infliximab (B evidence).
(4) Sulphasalazine is more efficacious than hydroxychloroquine (A2 evidence) and no significant differences have been found in the efficacy of sulphasalazine compared with leflunomide, methotrexate (A1 evidence), oral or injectable gold, and D-penicillamine (B evidence).
(5) Anti-TNF agents (infliximab and etanercept) have been shown to be efficacious in the treatment of RA (A1 evidence), and they show no significant differences in efficacy with respect to methotrexate (B evidence for infliximab and A1 for etanercept).
Alternative treatment in case of unsatisfactory response to initial treatment
| SIMPLIFIED CLINICAL CLASSIFICATION OF RA |
First-choice treatment used |
Alternative treatment in case of unsatisfactory response, in order of preference (supporting evidence) |
| No erosions |
<6 swollen joints |
Methotrexate |
Leflunomide (1) |
| Sulphasalazine |
Methotrexate (2)
Leflunomide (1) |
| Chloroquine |
Methotrexate (2)
Leflunomide (1) |
| >6 swollen joints |
Methotrexate |
Leflunomide (1) |
| Injectable gold |
Methotrexate (2)
Leflunomide (1) |
| Erosions present |
<6 swollen joints |
Methotrexate |
Leflunomide (1) |
| >6 swollen joints |
Methotrexate |
Leflunomide (1)
Anti-TNF agents (3)
Methotrexate + anti-TNF (4)
Methotrexate + chloroquine + sulphasalazine (5) |
| Leflunomide |
Methotrexate (2)
Anti-TNF agents (3)
Methotrexate + anti-TNF (4) |
| Methotrexate+injectable gold |
Leflunomide (1)
Anti-TNF (3) |
(1) Leflunomide (A1 evidence) has not shown differences in efficacy compared with methotrexate and sulphasalazine (A1 evidence).
(2) Methotrexate is more efficacious than oral gold (A1 evidence) or azathioprine (A2 evidence). No significant differences in efficacy have been found in methotrexate as compared to etanercept, leflunomide, sulphasalazine (A1 evidence), injectable gold (A2 evidence), cyclosporin, or infliximab (B evidence).
(3) Anti-TNF agents (infliximab and etanercept) have been shown to be efficacious in the treatment of RA (A1 evidence) in comparison with placebo, and they show no significant differences in efficacy as compared to methotrexate (B evidence for infliximab and A1 for etanercept).
(4) The combination of methotrexate+anti-TNF agents (infliximab or etanercept) has been shown to be more efficacious than methotrexate alone (B evidence).
(5) The combination of methotrexate+chloroquine+sulphasalazine has been shown to be more efficacious than methotrexate alone or chloroquine+sulphasalazine (A2 evidence).
In addition to the panel’s recommendations, there is scientific evidence regarding the efficacy of several drug combinations in case of failure of treatment with methotrexate or the antimalarials.
In case of failure with methotrexate, the following combinations have been shown to be more efficacious:
Methotrexate+cyclosporin (A1 evidence)
Methotrexate+chloroquine (A2 evidence)
Methotrexate+azathioprine (B evidence)
In case of failure with the antimalarials, the following combinations have been shown to be more efficacious:
Sulphasalazine+hydroxychloroquine (A2 evidence)
Methotrexate+hydroxychloroquine (B evidence)
Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs)
The NSAIDs are used to modify the symptoms of RA. The use of NSAIDs is recommended at disease onset, when a new DMARD is introduced, and when uncontrolled isolated symptoms persist despite good response to a DMARD.
The use of NSAIDs is recommended in the following cases: 1) At disease onset, if it is low risk (<6 swollen joints, no erosions, negative RF, and normal APRs), they can be used alone or in combination with corticosteroids for no longer than 3 months; 2) when a new DMARD is introduced, NSAIDs can be used until the DMARD is capable of controlling the disease and its symptoms, generally from 2 to 12 weeks depending on the time needed for the DMARD to reach effective therapeutic levels; and 3) when uncontrolled symptoms persist (painful inflammation or swelling or morning stiffness) despite DMARD treatment, and there is no evidence of inflammatory activity that would justify raising the DMARD dosage or changing to a new treatment. The need for gastric protectors should be evaluated in each patient.
Treatment with corticosteroids
The use of oral corticosteroids at low doses is recommended in patients in whom NSAIDs are not effective or are contraindicated for any reason. They can be used instead of NSAIDs or in association with them.
The corticosteroids should not replace treatment with DMARDs unless their possible role as a disease modifying agent should be shown. They are indicated as the treatment of choice only in the case of pseudopolymyalgic RA.
Corticosteroids should be used: 1) when NSAIDs are contraindicated or have a high risk of adverse effects (the elderly, associated morbidity); 2) as bridge therapy until the onset of DMARD action; 3) when NSAIDs do not effectively control inflammation (generally, by adding corticosteroids to the NSAID treatment); and 4) in the treatment of pseudopolymyalgic RA.
Treatment for pain
Analgesics are indicated to control pain. If there is no response, surgical treatment can be considered, especially to restore function and mobility.
Pain-control treatment should be instituted if pain persists despite the adoption of previous disease-control measures. Simple analgesics (e.g., acetaminophen, acetylsalicylic acid [ASA]) should be used first. If pain persists, dipyridamole, NSAIDs, or codeine may be used.
If pain is due to neuropathy, tricyclic antidepressants (amitryptiline) and some anticonvulsants (gabapentin or carbamazepine) may be used. When pain is very localized, local analgesics such as capsaicin cream may be used.
Surgical treatment should be considered when pain does not respond to pharmacological treatments and is due to joint destruction, producing changes in the patient’s functional capacity. If pain is intense, there is no response to previous analgesic treatments, and surgery is not an option, opiate analgesics may be administered.
Special considerations in the treatment of elderly patients
Kidney and liver function should be monitored in elderly patients, and the dosage intervals of the drugs eliminated by these routes should be adapted accordingly.
The dosage of drugs eliminated by the renal route should be adjusted in elderly patients. This is because: 1) Even in the absence of kidney disease, renal clearance in elderly individuals is decreased by 35-50%, and 2) The elderly, and especially those who suffer RA, have reduced muscular mass, which produces a decline in the production of creatinine. Thus, an elderly individual may have a normal creatinine value even though creatinine clearance is altered.
Aging may also alter hepatic function, thus the metabolization of drugs that are broken down in the liver may also be reduced.
The possible appearance of adverse effects and drug interactions should be monitored in elderly patients.
In general, elderly patients have more than one disease and need treatment with multiple drugs. This, together with the higher frequency of adverse reactions in the elderly, means there is an increased probability of drug interactions and contributes to a larger number of side effects.
Special considerations in the treatment of rheumatoid arthritis during pregnancy
Women of childbearing age should be informed of the possible effects of RA and its treatment on pregnancy.
There is no evidence that RA has a negative effect on pregnancy outcome. The symptoms of RA disappear during pregnancy in 70% of cases, to reappear early in the postpartum period. Nevertheless, the disease commonly fluctuates and, at the very least, cycles of analgesics will be required.
The use of NSAIDs during pregnancy and breastfeeding should be avoided insofar as possible. Corticosteroids can be used under controlled conditions. DMARDs should be managed on an individual basis, and should preferably be continued during pregnancy.
NSAIDs should be avoided in the first and last trimester and during breastfeeding. If necessary, NSAIDs with a short half-life (ibuprofen or ketoprofen) should be used.
There is no evidence that the corticosteroids produce serious adverse effects at average doses during pregnancy, except for promoting glucose intolerance, fluid retention, and hypertension. Consequently, they should be administered under controlled conditions.
With regard to the use of DMARDs during pregnancy and breastfeeding, in the case of aggressive disease, the DMARD should be maintained at the minimum effective dosage, unless it has been shown to affect the embryo, fetus, or infant.
Criteria for Response to Treatment
The objective of RA treatment is to induce complete disease remission or, alternatively, to achieve the best possible response.
RA patients who have spontaneous or drug-induced remissions in the course of their disease have a better medium-term outcome than those who have persistent clinical activity. However, the rates of complete remission with DMARDs and/or corticosteroids are low (18-25%) and are rarely prolonged. Complete disease remission, or at least attainment of the lowest possible level of inflammatory activity, is the only way to improve disease outcome.
Two basic approaches to defining clinical remission in RA have been described: the ACR criteria and the EULAR (European League Against Rheumatism) criteria.
ACR criteria for clinical remission
The presence of five or more of these criteria for at least 2 months is sufficient to classify a patient as in complete remission. Among the disadvantages of these criteria are the lack of guidelines on how to measure them, the fact that they are dichotomous, and that two of the criteria (fatigue and morning stiffness) are not included in the parameters recommended for the evaluation of RA patients.
EULAR criteria for clinical remission
The EULAR criteria use the DAS as a continuous variable of disease activity. A cut-off point below 1.6 on the DAS corresponds to the ACR definition of remission. Since the measurement scale is continuous, the cut-off point recommended by the EULAR may vary depending on future investigations.
Patients with RA should be clinically monitored for an indefinite period of time. Patients in complete disease remission should be seen every 6 months or 1 year, and patients with recent disease onset, frequent flare-ups, or persistent activity should be seen "on demand" (in general, every 1 or 2 months), depending on the treatment used and disease activity, until control is achieved.
To avoid an overload of patients, they can be seen in primary care during the periods between rheumatologist appointments to ensure clinical and laboratory monitoring and permit rapid referral to the specialist in case of disease reactivation and/or adverse effects.
Follow-up of patients with RA should be based on longitudinal monitoring of the parameters described in the initial evaluation: joint pain and inflammation, global pain assessment by the patient, global assessment of disease activity, functional disability, acute phase reactants, and radiologic damage.
One way to improve the quality of care for patients is to apply the treatment response criteria designed for use in clinical trials to daily clinical practice. Thus, it is proposed that the same parameters assessed at the initial evaluation be used to monitor patients and evaluate their response to treatment: pain and joint inflammation, global pain assessed by the patient, global disease activity assessed by the patient and by the physician, functional disability, and acute phase reactants. The same instruments used in the initial evaluation should be used in follow-up.
The physician’s subjective assessment of disease activity, although it is the most commonly used criterion in daily practice, is not recommended as the only criterion for response to treatment.
The treatment response criteria applied to individual patients should take into account: a) changes in disease activity and b) current level of activity. The clinician should evaluate the response to treatment, classifying it as satisfactory (complete remission of disease or sufficient even if not complete remission) or unsatisfactory (complete or almost complete lack of improvement). The evaluation can be made in accordance with any of the response criteria proposed in sections 5.4.1, 5.4.2, 5.4.3, and 5.4.4 of the original guideline document.
There is no published clinical experience in daily practice with any of the response indices developed for clinical trials. This guideline proposes the use of treatment response criteria based on two categories: satisfactory response, meaning complete remission of disease or a "sufficient" response, even though complete remission is not achieved, and unsatisfactory response, meaning complete or almost complete lack of improvement. The clinician can apply different response criteria to arrive at each of these categories. Two approaches that have been tested are described below: the ACR criteria for improvement and the EULAR definition of response. Other measures, such as the simplified Scott index and the Paulus criteria, are described in the guideline.
ACR response criteria
The ACR response criteria define a dichotomous result (response/no response) according to the following criteria:
These criteria are known as the ACR20, reflecting the need for a 20% improvement in each parameter, which is considered the clinically relevant cut-off point. The fact that the criteria do not consider the current activity level limits its application in daily clinical practice unless it is adapted to take this factor into account. Thus it is proposed that these criteria be applied with the following modification:
EULAR response criteria
The EULAR criteria use the disease activity scale (DAS), which takes into account both the degree of improvement and the patient’s current situation. It has been shown to be comparable in validity to the ACR response criteria in clinical trials. The definitions of satisfactory and unsatisfactory response, in accordance with the original DAS and DAS28, are shown in the original guideline document.
Surgical Treatment
The rheumatologist should consider surgical treatment in any of the following situations: 1) when articular function does not improve or is notably worse; 2) when incapacitating pain persists; or 3) when there are potentially serious or limiting neurological complications.
The joint prosthesis is the most efficient surgical means to arrest progressive loss of functional capacity. Synovectomy may produce slight improvement in the synovectomized joints, but this effect is not maintained at 3 years. Arthrodesis is a good control measure but is more limited from the functional point of view.
Appropriate medical treatment will reduce the indications for surgery and will improve the likelihood of surgical success. Consultation with an orthopedic surgeon should not always be an indication for surgery, but the exchange of opinions and clinical evaluation will help improve the patient’s clinical and functional status.
Before surgical intervention, an evaluation should be made of bone quality, the patient’s motivation and preferences, an estimate of how surgery would change the course of the disease, and the extent to which it can reconstruct articular function and make the patient more independent.
Rehabilitation Therapy
The objective of a rehabilitation program in RA patients is to improve pain, joint mobility, and performance of the activities of daily living. This is intended to prevent disability and maintain maximum personal independence. Rehabilitative techniques that can be used in treating RA patients are thermotherapy, physical exercise, prescription of splints, and occupational therapy.
Patients who undergo a rehabilitation program have 25 to 40% improvement in function.
Local Therapy
Local therapy in RA is indicated in joints with persistent disease activity despite adequate systemic control of the disease. The smaller the radiographic damage in a joint and the less systemic inflammatory activity of RA, the higher the probability that local treatment will have good results. Intra-articular infiltration with corticosteroids is the procedure of choice. Other procedures are radioisotopic synoviolisis and chemical synoviolisis.
Extra-articular Complications of Rheumatoid Arthritis
Amyloidosis
Secondary amyloidosis should be suspected in RA patients who develop proteinuria, renal failure, gastrointestinal symptoms, myocardiopathy and/or hepatomegaly, and in those having elevated phase reactants concurrent with little clinical activity.
Anemia
Anemia in RA is usually asymptomatic, therefore periodic blood cell counts should be obtained including erythrocyte, leukocyte and platelet counts, calculation of the mean corpuscular volume (MCV), reticulocyte count, and general liver and kidney function tests.
Cardiological complications
Cardiac involvement should be suspected in the presence of pericardial-type pain, heart failure, or conduction abnormalities. The two most frequent complications are pericarditis and myocarditis.
Osteoporosis
Osteoporosis should be suspected in the presence of vertebral or peripheral fractures not due to trauma. When RA is first diagnosed, all patients should be evaluated for the main risk factors for fracture and loss of bone mass; this analysis should include both RA-associated and independent risk factors.
Pulmonary complications
The presence of pleuritic pain, dyspnea, or hemoptysis is suggestive of pulmonary disease in RA patients. Pulmonary complications may include pleural disease, rheumatoid nodules, interstitial fibrosis, or bronchiolitis obliterans with organizing pneumonia.
Felty’s syndrome
Felty’s syndrome is indicated by the presence of splenomegaly, leukopenia (< 3,500/mm3), and neutropenia (<2,000/mm3) in patients meeting RA criteria.
Secondary Sjögren’s syndrome
A patient with RA is considered to have secondary Sjögren’s syndrome (SSS) if there are signs and symptoms indicative of xerophthalmia and xerostomia.
Vasculitis
Rheumatoid vasculitis is understood to be a set of vascular processes (periungual splinter hemorrhages, palpable purpura, polyarteritis nodosa) with variable outcome and treatment.
Definitions
Hadorn Scale for Rating the Quality of Scientific Evidence from Articles for Clinical Practice Guidelines (CPGs)
Level of Evidence A
- Well-conducted multicenter randomized controlled trials including 100 or more patients
- Well-conducted randomized trials with fewer than 100 patients, in one or more institutions
- Well-conducted cohort studies
Level of Evidence B
- Well-conducted case-controlled studies
- Poorly controlled or uncontrolled studies
- Conflicting evidence in favor of the recommendation
Level of Evidence C
- Expert opinion
Levels 1, 2, and 3 refer to a high level of evidence (A); levels 4, 5, and 6 refer to a level of evidence with potential biases that could invalidate the results (B); and level 7 is the evidence most vulnerable to potential biases (C).
Since only clinical trials were evaluated in the synthesis of the evidence on DMARD treatment for this guideline, the levels of evidence assigned are A1 (1 on the Hadorn scale), A2 (2 on the Hadorn scale), and B (5 on the Hadorn scale).
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