• July 14, 2009 - Sirolimus (Rapamune), Cyclosporine (Sandimmune or Neoral and generics), Mycophenolate mofetil (Cellcept and generics), Mycophenolic acid (Myfortic): The U.S. Food and Drug Administration (FDA) is requiring the makers of certain immunosuppressant drugs to update their labeling to reflect that immunosuppressed patients are at increased risk for opportunistic infections, such as activation of latent viral infections, including BK virus-associated nephropathy.
• September 11, 2008 - Rituxan (Rituximab): Genentech informed healthcare professionals of revisions to prescribing information for Rituxan regarding a case of progressive multifocal leukoencephalopathy (PML) leading to death in a patient with rheumatoid arthritis who received Rituxan in a long-term safety extension clinical study.

• The ACR criteria do not take current disease status into account, therefore the following modification proposed by the SER is recommended if they are applied. [5,D]

  The ACR criteria for improvement define a dichotomous outcome (response/no response) according to the following criteria:

  • Improvement of 20% or more in the tender joint count and in the swollen joint counts.
  • Improvement of 20% or more in at least 3 of the following parameters: ESR or CRP, physician global assessment of disease activity, patient global assessment of disease activity, patient pain assessment, physical disability.

  The ACR response criteria are likely to be modified in the near future; meanwhile, the following adaptation is proposed: (http://www.ser.es/):

  • Satisfactory response: fulfillment of the ACR20 criteria, fewer than 6 swollen joints, and absence of any patient circumstance that results in intolerable loss of functional capacity in the opinion of the patient or physician.
  • Unsatisfactory response: failure to meet the criteria for satisfactory response.

Subjective Physician Assessment of Disease Activity

• The subjective physician assessment of disease activity is the clinical criterion most commonly used in daily practice. It is not advisable to use it as the only response criterion. [5, D]

Frequency of Check-ups

• RA patients should be followed indefinitely: cases of established RA and in complete disease remission should be evaluated every 6-12 months; those with frequent outbreaks or with persistent activity and those who have recent-onset disease should be assessed "on demand" (in general, every 1-3 months) until remission is achieved or until reaching and maintaining the least possible inflammatory activity. [5, D]

Nursing Consultations

• The active incorporation of nursing staff is recommended from the outset to assist in the evaluation of disease inflammatory activity, facilitate early detection of side effects and comorbidity, and improve health education. [5, D]

Periodic Check-ups and Administration of Questionnaires

• Joint counts and other parameters included in the systematic clinical evaluation of the patient should be carried out in the nursing consultation. [5, D]

Monitoring the Adverse Effects of Disease-Modifying Anti-rheumatic Drugs (DMARDs) and Treatment with Biologics

• It is recommended that adverse treatment effects be monitored in the nursing consultation. The rheumatologist who is responsible for the patient should be informed of any possible adverse effect, whether objective or subjective. [5, D]

Patient Education

• A patient education program should be implemented that includes at least the following aspects: 1) monitoring and control of the adverse effects of DMARDS and biologic treatments; 2) exercise; 3) pain control; 4) joint protection. [5, D]

RA Comorbidity

• The rheumatologist is responsible for controlling the inflammatory process and should monitor RA-associated comorbidity with the support of the primary care physician and with recourse to other specialists when needed. [5, D]

RA Complications

Amyloidosis

• Secondary amyloidosis should be suspected in RA patients who develop proteinuria, renal failure, gastrointestinal symptoms, myocardiopathy and/or hepatomegaly, and in those who have elevated acute phase reactants (APR) concurrent with little clinical activity. [5, D]
• Treatment should be preventive and should aim to suppress the inflammatory activity of RA. There is no single clear standard for the treatment of established amyloidosis. Several published case series have shown important improvements in proteinuria and renal function in patients with amyloidosis secondary to RA treated with anti-tumor necrosis factor (anti-TNF), which, given its lower toxicity, is a good treatment alternative. [4, C]

Anemia

• Periodic blood cell counts and general liver and kidney function tests are recommended. [5, D]
• Chronic anemia in conjunction with RA does not usually require treatment. Oral iron supplements are not indicated, except in cases of ferropenic anemia. The use of erythropoietin is controversial. [5, D]

Cardiological Complications

• RA-related cardiac involvement should be suspected in the presence of pericardial pain, heart failure or conduction abnormalities. [5, D]
• Pericarditis should be treated initially with full doses of nonsteroidal anti-inflammatory drugs (NSAIDs) (150 mg/day of indomethacin); if this is not effective, prednisone (1mg/kg/day); the rare cases of cardiac tamponade should be treated with evacuation by pericardiocentesis. [4, C]
• In addition to treatment for heart failure, myocarditis requires treatment with high-dose prednisone. [4, C]

Pulmonary Complications

• Pulmonary disease should be suspected if there is pleuritic pain, progressive or recent-onset dyspnea, or hemoptysis. [5, D]
• In the case of pleural involvement, thoracocentesis is recommended to obtain an exudate and rule out other diseases (infection or neoplasia). [5, D]
• Pleural involvement should be treated with full-dose or medium-dose steroids (10-20 mg/day of prednisone). [4, C]
• Rheumatoid nodules do not require treatment in the absence of complications. [5, D]
• Recent-onset (acute) interstitial involvement is treated with prednisone (1-1.5 mg/kg/day). If there is no response, patients may be treated with cyclophosphamide or azathioprine. Bronchiolitis obliterans organizing pneumonia (BOOP) is treated with prednisone (1.5 mg/kg/day). [4, C]

Felty's Syndrome

• Treatment for Felty's syndrome requires comprehensive control of RA inflammatory activity. As a specific measure, the use of filgrastim is recommended when the absolute neutrophil count is lower than 1,000/mm³ and the patient has a history of severe infections associated with the disease. [5, D]

Secondary Sjögren's Syndrome (SSS)

• There are no specific recommendations for modifying the course of SSS in RA. The recommendations in this guideline include symptomatic treatment of xerophthalmia and xerostomia. Dental and ophthalmological examinations at least every 6 months are recommended. [5, D]

Vasculitis

• Palpable purpura should be treated with full-dose NSAIDs and medium-low doses of prednisone (15-30 mg/day). [4, C]
• Polyarteritis nodosa is treated initially with high-dose steroids (40-120 mg/day of prednisone). If there is no response, cyclophosphamide should be added (2-3 mg/kg/day orally or 0.5-1 g/m² in intravenous pulses of 2 to 4 weeks). [4, C]

Comorbidity Not Directly Related with RA

Infections

• Extreme precautions should be exercised in RA patients to prevent infections. Recommended measures include receipt of routine vaccinations, but never with attenuated microorganisms if the patient is receiving immunosuppressive treatment [4, C], avoiding contacts with tuberculosis patients and receiving chemoprophylaxis with isoniazid as needed [2.b, B], and practicing scrupulous dental hygiene. [2.b, B]

Tuberculosis

The following recommendations of the Spanish Society of Rheumatology and the Spanish Medicines Agency (AEME in Spanish) have made it possible to reduce the risk of tuberculosis (TB) activation in patients undergoing anti-tumor necrosis factor (anti-TNF) treatment to nearly normal levels:

Table: SER and AEME Recommendations to Control the Risk of TB in Patients with Anti-TNF Treatment

Table: SER and AEME Recommendations According to PPD Results

Cardiovascular Complications

• Individual risk factors for cardiovascular (CV) complications should be identified and treated: age, male sex, highly active arthritis, smoking, arterial hypertension, hypercholesterolemia and history of CV episode. [1.b, A]

Osteoporosis

• When RA is first diagnosed, the principal risk factors for fracture and loss of bone mass should be analyzed; if any are present, bone densitometry is indicated. [5, D] (See Table 19 in the original guideline document).
• The first-line treatment options for osteoporosis are alendronate and risedronate, with cyclic etidronate or calcitonin as alternatives. [5, D]
• Hormone treatment is not indicated. [5, D]

Table: Risk Factors for Osteoporosis

Neoplasias

• Discontinuation of all tobacco use is indicated in all RA patients. [5, D]
• Anti-TNFs are not recommended in patients with a personal history of lymphoma. [4, C]
• In patients with a personal history of lymphoma, the risk/benefit ratio should be carefully evaluated before deciding to use a TNF antagonist. [5, D]
• History of a malignant solid tumor in the last 5 years is a contraindication for the use of nti-TNF agents. [5, D]
• If there is history of a malignant solid tumor longer than 5 years previously, the physician should consult the specialist in oncology about the biopathology of the tumor. [5, D]
• An RA patient who develops a tumor should discontinue all DMARDs except antimalarials, gold salts, and sulfasalazine. [5, D]

Pharmacological Treatment

Pharmacological Treatment of Recent-Onset Rheumatoid Arthritis

• All RA patients should be treated with a DMARD as soon as the clinical diagnosis of the disease is established, regardless of whether they meet the ACR classification criteria. [5, D]
• The initial treatment recommended in all patients who have not been previously treated with a DMARD is methotrexate (MTX), due to its excellent safety and efficacy profile. [5, D]
• For optimal use of MTX as a remission-inducing agent in early RA, a rapid step-up dose to 20 or 25 mg weekly is recommended by 3-4 months after initiation of MTX. In refractory cases, MTX bioavailability should be assured by subcutaneous administration. [5, D]
• Nonetheless, given the clinical complexity of RA, the panel considers that, in some clinical situations, initial DMARD treatment may consist of using other drugs that have also been shown to control signs and symptoms of the disease and to delay radiologic progression. [5, D]
• In early RA with no markers of poor outcome (radiologic erosions, RF, anti-CCP antibodies, absence of extra-articular disease, HAQ over 1 or high inflammatory burden), it is acceptable to begin treatment with other DMARDs that have a lower toxicity profile or are easier to monitor for side effects; typical examples of these are the anti-malarials or sulfasalazine (SSZ). [5, D]
• In early RA that is expected to be especially incapacitating due to characteristics of the disease, the patient, or the patient's type of employment, initial combination therapy with MTX and an anti-TNF agent may be indicated; the objective of this treatment is to induce rapid remission and try to withdraw the anti-TNF agent and maintain RA remission with MTX in monotherapy. [5, D]

Refer to Table 21 in the original guideline document for recommended doses and commercial names of DMARDs.

Changes in Treatment

• Treatment failure or toxicity should be evaluated in a maximum of 3 months and a consequent change in treatment should be considered. The objective of treatment should be to maintain a Disease Activity Score using a count of 28 joints (DAS28) of <3.2. [5, D]
• If response to MTX is unsatisfactory after reaching the maximum dosage and assuring the bioavailability of the agent, the panel recommends the use of leflunomide (LEF) or SSZ or an anti-TNF agent as the second step in the treatment ladder, either replacing or in addition to MTX. If MTX toxicity is such as to oblige its withdrawal, the panel recommends using LEF or SSZ or an ant-TNF agent as the second step on the treatment ladder. [5, D]
• In patients for whom the previously described guidelines are not useful due to lack of efficacy, toxicity or other reasons, use of any of the DMARDs, combinations or other biologic agents is recommended; if these fail, experimental treatments should be tried. [5, D]
• Other biologic agents such as abatacept (ABT) or rituximab (RTX) are reasonable alternatives in patients who have not responded to or who have experienced toxicity with one or more anti-TNF agents.

Treatment with Glucocorticoids

• In recent-onset RA the use of low-dose oral glucocorticoids (GC) is the recommended disease-modifying therapy, always in combination with a DMARD. [1.b, A]
• In RA of long duration, the use of low-dose oral glucocorticoids is recommended as anti-inflammatory therapy for symptom control while waiting for the DMARDs to take effect. [5, D]
• Given the association between glucocorticoid use and rapid loss of bone mass, it should at a minimum be used jointly with Vitamin D and calcium, and other preventive treatments for osteoporosis should be evaluated (see section III.3.2.c. in the original guideline document) if treatment is expected to exceed 3 months. [5, D]
• The use of intra-articular glucocorticoids is essential in the management of joints that are persistently inflamed despite good therapeutic response to the DMARD regimen.

Treatment with Non-Steroidal Anti-Inflammatories (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 occasionally when uncontrolled isolated symptoms persist despite good response to a DMARD. [5, D]. The need for continuous use of NSAIDs in a patient with RA should be interpreted as inadequate control of inflammatory activity and should, therefore, lead to reassessment of the DMARD regimen. [5, D]
• All NSAIDs should be used at the full dose for at least 1 week before considering the treatment to have failed. Once symptoms have been controlled, the minimum effective dose should be used. [5, D]
• There is no evidence that some NSAIDs are better than others, therefore the one that best fits the patient characteristics should be used. [5, D]
• The need for co-treatment with gastric protectors should be evaluated on an individual basis. [5, D]

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. [5, D]

Treatment of RA in Special Situations

Elderly Patients

Monitoring Kidney and Liver Function

• 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. [5, D]

Monitoring Adverse Effects and Drug Interactions

• The possible appearance of adverse effects and interactions among drugs taken regularly should be monitored in elderly patients. [5, D]

Pregnancy and Breastfeeding

Prevention

• Women of childbearing age should be informed of the possible effects of RA on pregnancy, in particular, because of the implications for treatment. [5, D]

Drug Management during Pregnancy and Breastfeeding

• 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. [5, D]

Table 30 in the original guideline document shows the considerations to be taken into account with regard to DMARD use during pregnancy and breastfeeding.

For information about the safety of pharmacological treatments, including recommendations for monitoring, see Section VI and Table 31 in the original guideline document.

Other Treatments

Intra-articular Treatment

Types of Intra-articular Treatment

• The recommended local treatment of choice is intra-articular infiltration with slow-release steroids. When steroid infiltrations have failed (3 consecutive infiltrations 4 weeks apart), isotopic synovialitis or chemical synovitis with osmic acid can be considered. Before starting local treatment, the presence of infection should be reasonably ruled out. [5, D]

Rehabilitation in Rheumatoid Arthritis

Non-pharmacological Interventions

Therapeutic Exercise

• From the time of diagnosis a program of aerobic physical exercise is recommended. It should initially be supervised to adapt it to the individual's level of physical preparation and the specific joint and extra-articular circumstances stemming from the disease and comorbidities. [1.a, A]
• Aerobic exercises can be combined with muscle strengthening exercises (regional or general), and exercises to improve flexibility, coordination and manual dexterity.

Physical Treatments (Passive Modalities)

• Low level laser therapy and transcutaneous electrical nerve stimulation (TENS), used alone and independently, are effective in reducing pain in the short term (TENS has the advantage of easy application with portable units that can be used at home). [1.a, A]
• The combination of paraffin (thermotherapy) and active exercises also appears to be effective against pain. Data on ultrasound, muscular electrostimulation and magnetotherapy remain insufficient to recommend them for routine use, but they should be considered in selected cases that do not respond to other alternatives. The application of thermotherapy alone and the local application of cold do not appear to offer any clinical benefit. [2.b, B]

Integral Occupational Therapy

• In patients with important functional limitations, usually those with advanced disease, a lasting improvement has been observed. [1.b, A]

Joint Protection and Energy Conservation Programs

• In advanced phases of RA it is useful to instruct the patient about rules for joint protection. Teaching strategies to conserve energy is indicated only in patients in whom fatigue is an important symptom. [4, C]

Assistive Devices

• The use of assistive devices for important tasks should be evaluated in RA patients who have difficulties carrying out basic or instrumental activities of daily living due to weakness or lack of manual dexterity (who do not improve with an exercise program), or due to pain (that is not controlled with other therapies). [5, D]

Orthotics

Splints or Upper Limb Orthotics

• In periods of active inflammation (with the main objective of avoiding pain and reducing inflammation), static orthotics can be used (at first during the whole day and later only at night). If the patient has functional problems these can be combined during the day (part time) with functional orthotics adapted to the specific problem and to the anatomical region interfering with function. [4, C]
• Their efficacy should be evaluated periodically, and orthotics that do not meet expectations should be rejected. [5, D]

Lower Limb Orthotics

• Pain of the forefoot can be improved with hard and soft orthotics. Hard orthotics improve pain in the hindfoot in the initial phase of the disease. Use of a special model can prevent the development and progression of hallux valgus. Shoes with special widths improve the results. [1.a, A]
• Studies of orthotics are highly heterogeneous, and it is not possible to establish which type of orthotic is the most appropriate for each type of involvement. [5, D]

Balneotherapy

• Balneotherapy can be recommended in cases of polyarticular involvement without active disease, where other more accessible therapies have been ineffective. [2.b, B]

Combination Treatments. Multidisciplinary Approaches

• It is important that all professionals who participate in the treatment of the RA patient have a coordinated approach focusing on specific problems, with appropriate assessment of the effects of interventions. [5, D]

Surgical Treatment in RA

• Before performing surgical treatment, several factors should be considered: bone quality, the patient's preferences and level of motivation, estimation of the extent to which disease progression can be modified by surgery, and estimation of the degree to which surgical treatment can reconstruct joint function and improve the patient's independence. [5, D]
• The joint prosthesis is the most effective surgical measure to halt the progressive loss of functional capacity. Joint replacement, in whatever joint, should be performed before irreversible deformities become established. [5, D]

Note: This section has not been updated since GUIPCAR-2001.

Definitions:

Levels of Evidence

See Table 1, "Levels of Evidence, Oxford Centre for Evidence-Based Medicine," and the accompanying explanatory notes in the original guideline document.

Grades of Recommendation*

1. Based on the results of consistent level 1 studies
2. Based on the results of consistent level 2 or 3 studies or on extrapolations** from level 1 studies
3. Based on the results of level 4 studies or on extrapolations* from level 2 or 3 studies
4. Based on the results of level 5 studies or on troublingly inconsistent or inconclusive studies of any level

*See Table 1 in the original guideline document for an explanation of the levels of evidence according to the Oxford Classification for Evidence-Based Medicine

**"Extrapolations" are where data is used in a situation which has potentially clinically important differences than the original study situation.

Electronic copies: Available in Spanish and in English from the Spanish Society of Rheumatology Web site.

Print copies (Spanish): Available from the Spanish Society of Rheumatology. C/Marqués del Duero, 5 - 1st floor, 28001 Madrid, Spain; Telephone: +34 91 5767799; Fax: +34 91 5781133; e-mail: ser@ser.es.

• Quick reference guide (Spanish). Madrid: Spanish Society of Rheumatology; 2007. 18 p. Electronic copies: Available from the Spanish Society of Rheumatology Web site.
• Recommendations for rheumatoid arthritis (Spanish). Madrid: Spanish Society of Rheumatology; 2007. 8 p. Electronic copies: Available from the Spanish Society of Rheumatology Web site.

Print copies (Spanish): Available from the Spanish Society of Rheumatology. C/Marqués del Duero, 5 - 1st floor, 28001 Madrid, Spain; Telephone: +34 91 5767799; Fax: +34 91 5781133; e-mail: ser@ser.es.

Additionally, a series of indicators for rheumatoid arthritis (RA) management and a set of data collection instruments for parameters used in initial evaluation and monitoring of RA patients are available in the original guideline document.

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