Source: GUIPCAR Group. Clinical practice guideline for the management of
	rheumatoid arthritis. Quick Reference Guide. Madrid: Spanish Society of
	Rheumatology; 2001. 19 p.
	CLINICAL PRACTICE GUIDELINE FOR THE MANAGEMENT OF RHEUMATOID ARTHRITIS
	QUICK REFERENCE GUIDE
	Contents
	   * DIAGNOSING RHEUMATOID ARTHRITIS
	   * INITIAL EVALUATION
	   * CLASSIFYING RHEUMATOID ARTHRITIS
	   * MEDICAL TREATMENT OF RHEUMATOID ARTHRITIS
	   * CRITERIA FOR RESPONSE TO TREATMENT
	   * SURGICAL TREATMENT
	   * REHABILITATIVE THERAPY
	   * LOCAL THERAPY
	   * EXTRA-ARTICULAR COMPLICATIONS OF RHEUMATOID ARTHRITIS
	Introduction
	In 1998 the Spanish Society of Rheumatology (SER) decided to develop a
	Clinical Practice Guideline (CPG) to help physicians make decisions
	about the diagnosis and treatment of patients with rheumatoid arthritis
	(RA). This initiative of the SER was in response to a phenomenon
	frequently seen in clinical practice: the large variability in the use
	of diagnostic, therapeutic and rehabilitative procedures. The enormous
	amount of information produced as a result of a growing number of
	studies, their variable methodological quality, and the complexity of
	comparing the results of different studies constitute a major obstacle
	for clinicians in keeping up to date on important knowledge in their
	field. This situation prompted the idea of producing a CPG for the
	management of RA (GUIPCAR), which was undertaken by the Health Services
	Research Unit (UISS) of the Carlos III Health Institute. This project
	took 2 years to complete. During this time, the UISS became a private
	company with the name of Advanced Research Techniques in the Health
	Services (TAISS).
	RA is a systemic disease, of unknown etiology, which is characterized by
	chronic inflammation of the diarthrodial joints and is usually
	associated with severe morbidity. It is estimated to affect some 200,000
	persons in Spain, with 20,000 new cases occurring each year. The quality
	of life is reduced in most patients, who usually experience changes in
	functional capacity, with work disability and increased mortality.
	RA also produces an enormous social cost. It has been estimated that the
	annual cost of this disease in Spain exceeds 200 billion pesetas
	(US$1.04 million), of which 65 billion pesetas ($338.5 million) are
	devoted to health expenditures.
	There is evidence of large variability in the management of RA in Spain;
	this variability depends not only on patient or disease characteristics,
	but also on characteristics of the hospital, department, or physician
	providing patient care. For example, the mean number of patient visits
	in one center may be double that of another, after adjusting for disease
	severity and functional class. Even more variability has been seen in
	other areas, such as the use of diagnostic tests or management of
	treatment. These facts may suggest that some diagnostic or therapeutic
	procedures are of uncertain value while other, appropriate procedures
	may be underused.
	Objectives
	The main objective of this guideline is to develop high quality criteria
	for the treatment of RA and to reduce the variability that is not
	dependent on patient characteristics.
	Contents and Methodology
	This guideline describes the diagnostic and management strategies that
	an expert panel considered appropriate for the evaluation and treatment
	of patients with RA. It focuses on RA in adults (excluding juvenile RA)
	and includes diagnosis, evaluation, prognosis, and treatments such as
	drugs, rehabilitation, and surgery. It does not cover other treatments
	such as acupuncture, and only briefly treats extra-articular
	complications of RA such as amyloidosis, anemia, or Sjgren's syndrome.
	The guideline recommendations can be applied in both the hospital and
	outpatient setting except for some, such as the guidelines for surgery,
	which obviously can only be performed in specialized centers. This
	guideline is intended for rheumatologists and recommends that the
	diagnosis, monitoring, and treatment of RA be carried out by physicians
	who are trained to identify patients in the early phases of disease, to
	evaluate the disease stage, to suggest appropriate treatment for each
	stage in the evolution of the disease, and to measure the response to
	treatment.
	The recommendations for treatment with disease-modifying anti-rheumatic
	drugs (DMARDs) in this guideline are based on a synthesis of the best
	available scientific evidence after making a systematic review of the
	literature. The rest of the recommendations or considerations are based
	on scientific evidence obtained without a systematic literature review,
	or on the opinions of the expert panel.
	Using the Quick Reference Guide
	This quick reference guide describes the most important recommendations
	contained in the guideline. The recommendations are presented in this
	summary in an abbreviated form. Readers should refer to the text of the
	guideline to see the complete recommendation, discussion, levels of
	evidence, and bibliographic references. This quick reference guide
	includes a simplified algorithm. The algorithms included at the end of
	the guideline allow the user to follow a logical decision-making process
	in managing the patient.
	DIAGNOSING 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:
	   1. Morning stiffness lasting at least one hour before maximal
	      improvement, for at least 6 consecutive weeks.
	   2. 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.
	   3. Swelling or effusion, observed by a physician, in the proximal
	      interphalangeal, metacarpophalangeal, or wrist joints, for at
	      least 6 consecutive weeks.
	   4. 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.
	   5. Subcutaneous nodules over bony prominences or extensor surfaces,
	      or in juxta-articular regions, observed by a physician.
	   6. Demonstration of serum rheumatoid factor (RF) detected by any
	      method that has been positive in less than 5% of control subjects.
	   7. 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, NSAIDs, corticosteroids, and 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 (GOT, GPT,
	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 guideline),
	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
	following formula:
	DAS = 0.54 (RI) + 0.065 (NSJ44) + 0.33 (In ESR) + 0.0072 (PGA)
	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:
	DAS28 = 0.56 (NPJ28) + 0.28 (NSJ28) + 0.70 (In ESR) = + 0.014 (PGA)
	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 (Greater than
	or equal to 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 immunosuppresants, anti-TNF
	agents, or corticosteroids. If latent tuberculosis infection is present,
	prophylactic treatment with isoniazide is recommended.
	CLASSIFYING RHEUMATOID 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/greater than or equal to 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
	greater than or equal to 1, and high titers of positive RF). Each patient,
	according to the initial disease characteristics, should begin a specific
	treatment option (see chapter 4).
	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.
	At 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
	   * No erosions
          	* <6 swollen joints
	Recommended treatment of first choice (in order of preference)
                       * Methotrexate (1)
                       * Sulphasalazine (2)
                       * Chloroquine (3)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * No erosions
          	* Greater than or equal to 6 swollen joints
	Recommended treatment of first choice (in order of preference)
                       * Methotrexate (1)
                       * Injectable gold (4)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * Erosions present
          	* <6 swollen joints
	Recommended treatment of first choice (in order of preference)
                       * Methotrexate (1)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * Erosions present
          	* Greater than or equal to 6 swollen joints
	Recommended treatment of first choice (in order of preference)
                       * 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 guideline); 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
	   * No erosions
          	* <6 swollen joints
	First-choice treatment used
                       * Methotrexate
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
                            * Leflunomide (1)
                            * Injectable gold (2)
	                    * Sulphasalazine (4)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * No erosions
          	* <6 swollen joints
	First-choice treatment used
                       * Sulphasalazine
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
                            * Methotrexate (3)
                            * Injectable gold (2)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * No erosions
          	* <6 swollen joints
	First-choice treatment used
                       * Chloroquine
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
                            * Methotrexate (3)
                            * Injectable gold (2)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * No erosions
          	* Greater than or equal to 6 swollen joints
	First-choice treatment used
                       * Methotrexate
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
                            * Leflunomide (1)
                            * Injectable gold (2)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * No erosions
          	* Greater than or equal to 6 swollen joints
	First-choice treatment used
                       * Injectable gold
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
                            * Methotrexate (3)
                            * Leflunomide (1)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * Erosions present
          	* <6 swollen joints
	First-choice treatment used
                       * Methotrexate
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
                            * Leflunomide (1)
                            * Injectable gold (2)
                            * Sulphasalazine (4)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * Erosions present
          	* Greater than or equal to 6 swollen joints
	First-choice treatment used
                       * Methotrexate
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
                            * Leflunomide (1)
                            * Injectable gold (2)
                            * Sulphasalazine (4)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * Erosions present
          	* Greater than or equal to 6 swollen joints
	First-choice treatment used
                       * Leflunomide
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
                            * Methotrexate (3)
                            * Anti-TNF (5)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * Erosions present
          	* Greater than or equal to 6 swollen joints
	First-choice treatment used
                       * Methotrexate+injectable gold
	Alternative treatment in case of toxicity, in order of preference (supporting evidence)
                            * 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
	   * No erosions
          	* <6 swollen joints
	First-choice treatment used
                       * Methotrexate
	Alternative treatment in case of unsatisfactory response, in order of preference (supporting evidence)
                            * Leflunomide (1)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * No erosions
          	* <6 swollen joints
	First-choice treatment used
                       * Sulphasalazine
	Alternative treatment in case of unsatisfactory response, in order of preference (supporting evidence)
                            * Methotrexate (2)
                            * Leflunomide (1)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * No erosions
          	* <6 swollen joints
	First-choice treatment used
                       * Chloroquine
	Alternative treatment in case of unsatisfactory response, in order of preference (supporting evidence)
                            * Methotrexate (2)
                            * Leflunomide (1)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * No erosions
          	* Greater than or equal to 6 swollen joints
	First-choice treatment used
                       * Methotrexate
	Alternative treatment in case of unsatisfactory response, in order of preference (supporting evidence)
                            * Leflunomide (1)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * No erosions
          	* Greater than or equal to 6 swollen joints
	First-choice treatment used
                       * Injectable gold
	Alternative treatment in case of unsatisfactory response, in order of preference (supporting evidence)
                            * Methotrexate (2)
                            * Leflunomide (1)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * Erosions present
          	* <6 swollen joints
	First-choice treatment used
                       * Methotrexate
	Alternative treatment in case of unsatisfactory response, in order of preference (supporting evidence)
                            * Leflunomide (1)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * Erosions present
          	* Greater than or equal to 6 swollen joints
	First-choice treatment used
                       * Methotrexate
	Alternative treatment in case of unsatisfactory response, in order of preference (supporting evidence)
                            * Leflunomide (1)
                            * Anti-TNF agents (3)
                            * Methotrexate+anti-TNF (4)
                            * Methotrexate+chloroquine+sulphasalazine (5)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * Erosions present
          	* Greater than or equal to 6 swollen joints
	First-choice treatment used
                       * Leflunomide
	Alternative treatment in case of unsatisfactory response, in order of preference (supporting evidence)
                            * Methotrexate (2)
                            * Anti-TNF agents (3)
                            * Methotrexate+anti-TNF (4)
	SIMPLIFIED CLINICAL CLASSIFICATION OF RA
	   * Erosions present
          	* Greater than or equal to 6 swollen joints
	First-choice treatment used
                       * Methotrexate+injectable gold
	Alternative treatment in case of unsatisfactory response, in order of preference (supporting evidence)
                            * 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.,
	paracetamol, 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 (gabapentine 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 criteria.
	ACR criteria for clinical remission
	   * Morning stiffness absent or not exceeding 15 minutes
	   * No fatigue
	   * No joint pain (by clinical history)
	   * No joint tenderness
	   * No soft tissue swelling in joints or tendon sheaths
	   * Normal erythrocyte sedimentation rate.
	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.
	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:
	   * At least 20% improvement in the painful joint count and in the
	     swollen joint count; and
	   * At least 20% improvement in at least three of the following
	     parameters: ESR or APR, physician's global assessment of disease
	     activity, patient's global assessment of disease activity,
	     patient's assessment of pain, and physical disability.
	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:
	   * Satisfactory response: Meeting the following three criteria: 1)
	     ACR20; 2) fewer than 6 swollen joints; and 3) no impairment of any
	     joint producing intolerable loss of functional capacity in the
	     opinion of the patient or physician.
	   * Unsatisfactory response: Not meeting the criteria for
	     satisfactory response.
	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 accompanying tables.
	EULAR DEFINITION OF RESPONSE (DAS)
	Current DAS
	   * <2.4
	DAS decrease
	   * >1.2
          	* Satisfactory
	   * 0.6-1.2
          	* Unsatisfactory
	   * <0.6
          	* Unsatisfactory
	Current DAS
	   * 2.4-3.7
	DAS decrease
	   * >1.2
          	* Unsatisfactory
	   * 0.6-1.2
          	* Unsatisfactory
	   * <0.6
          	* Unsatisfactory
	Current DAS
	   * >3.7
	DAS decrease
	   * >1.2
          	* Unsatisfactory
	   * 0.6-1.2
          	* Unsatisfactory
	   * <0.6
          	* Unsatisfactory
	EULAR DEFINITION OF RESPONSE (DAS28)
	Current DAS28
	   * <3.2
	DAS28 decrease
	   * >1.2
          	* Satisfactory
	   * 0.6-1.2
          	* Unsatisfactory
	   * <0.6
          	* Unsatisfactory
	Current DAS28
	   * 3.2-5.1
	DAS28 decrease
	   * >1.2
          	* Unsatisfactory
	   * 0.6-1.2
          	* Unsatisfactory
	   * <0.6
          	* Unsatisfactory
	Current DAS28
	   * >5.1
	DAS28 decrease
	   * >1.2
          	* Unsatisfactory
	   * 0.6-1.2
          	* Unsatisfactory
	   * <0.6
          	* Unsatisfactory
	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.
	REHABILITATIVE 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/mm^3 ), and neutropenia (<2,000/mm^3 ) in patients
	meeting RA criteria.
	Secondary Sjgren's syndrome
	A patient with RA is considered to have secondary Sjgren'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.
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