Initial treatment of mildly active rheumatoid arthritis in adults

Initial treatment of mildly active rheumatoid arthritis in adults

Authors
Peter H Schur, MD
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Stanley Cohen, MD

Section Editor
James R O'Dell, MD

Deputy Editor
Paul L Romain, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2016. &#124 This topic last updated: May 13, 2014.

INTRODUCTION — The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis and the prevention of joint damage. Joint damage, which may ultimately result in disability, begins early in the course of disease, and patients are less likely to completely respond to therapy the longer active disease persists [1]. Improved outcomes have resulted from the availability and use of potent and well-tolerated disease-modifying antirheumatic drugs (DMARDs) used alone and in combination to aggressively induce and maintain tight control of disease [2-10]. These DMARDs can control synovitis and slow, or even stop, radiographic progression [2,9,11,12]. (See "Clinical manifestations of rheumatoid arthritis" and "Pathogenesis of rheumatoid arthritis" and "General principles of management of rheumatoid arthritis in adults", section on 'Tight control'.)
These observations regarding the course of disease and the efficacy of newer therapeutic approaches, coupled with limits in the ability to accurately identify individuals with a poor prognosis, support our view that every patient with established active RA should be treated with DMARDs at the earliest stage of disease, ideally within less than three months of symptom onset. (See "General principles of management of rheumatoid arthritis in adults", section on 'Prognosis' and "General principles of management of rheumatoid arthritis in adults", section on 'Early use of DMARDs'.)
The choice of therapeutic agents, including both antiinflammatories and DMARDs, is influenced by the degree of disease activity, the risk of a particular medication for a given patient, and patient preferences. The initial treatment of patients with mildly active RA will be reviewed here. The diagnosis and differential diagnosis of RA, the general principles of management, an overview of the therapy of RA, the initial treatment of moderately to severely active RA, and the treatment of disease resistant to initial therapy are presented separately. (See "Diagnosis and differential diagnosis of rheumatoid arthritis" and "General principles of management of rheumatoid arthritis in adults" and "Initial treatment of moderately to severely active rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy".)
DEFINITION OF MILDLY ACTIVE RA — Patients with mildly active rheumatoid arthritis (RA) typically meet American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria for RA and have all of the following (see "Diagnosis and differential diagnosis of rheumatoid arthritis"):
●Fewer than five inflamed joints
●Mildly elevated or normal erythrocyte sedimentation rate and C-reactive protein levels
●No extraarticular disease
●No evidence of erosions or cartilage loss on plain radiographs of the hands, wrists, and feet
●Low levels of measures of disease activity such as the Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), or Routine Assessment of Patient Index Data (RAPID) (see "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice")
Most of these patients will lack poor prognostic features such as rheumatoid factor or antibodies to cyclic citrullinated peptides (CCP).
GENERAL PRINCIPLES — There are several general principles important in the management of all patients with rheumatoid arthritis (RA). These principles are discussed in detail elsewhere (see "General principles of management of rheumatoid arthritis in adults"). Briefly, these include:
●Achievement and maintenance of tight control of disease activity, defined as remission or a state of minimal disease activity, without compromising safety
•Frequent monitoring of activity by assessing history, the physical examination, acute phase reactants, and use of measures of disease activity (see "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice")
•The prompt use of more aggressive disease-modifying antirheumatic drug (DMARD) therapy (eg, methotrexate [MTX] in patients being treated with hydroxychloroquine [HCQ] or sulfasalazine [SSZ]) in patients with failure to induce either remission or minimal disease activity
●Treatment of all patients diagnosed with RA with DMARD therapy
●Use of antiinflammatory therapies, including nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids, to help control symptoms until DMARDs take effect
●Evaluation and ongoing care by a rheumatologist
NONPHARMACOLOGIC AND PREVENTIVE THERAPIES — A number of nonpharmacologic measures and other medical interventions are important in the comprehensive management of rheumatoid arthritis (RA), in addition to antiinflammatory and antirheumatic drug therapies. These interventions, including patient education, vaccinations, cardiovascular risk reduction, and others, are discussed in detail elsewhere. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis".)
PHARMACOLOGIC THERAPY — We use hydroxychloroquine (HCQ) and/or sulfasalazine (SSZ) as the initial disease-modifying antirheumatic drug (DMARD) in most patients with mildly active rheumatoid arthritis (RA), particularly those with minimal or low levels of disease activity and those who are seronegative for rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibodies. These two drugs do not impair female fertility and are relatively safe if continuing use is essential in pregnancy; thus, they are especially suitable for female patients who are planning a family. Additionally, we use nonsteroidal antiinflammatory drugs (NSAIDs) or glucocorticoids in many patients on a temporary basis to quickly achieve control of signs and symptoms of disease, in addition to starting the DMARD. We then taper and withdraw the antiinflammatory medications once the DMARDs have taken effect. (See 'Use of DMARDs' below and 'Antiinflammatory agents' below and "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Hydroxychloroquine' and "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation", section on 'Sulfasalazine'.)
If patients have greater disease activity, or if an adequate trial (12 to 24 weeks) of these medications proves inadequate, we then initiate therapy with another DMARD, usually methotrexate (MTX), or a combination of DMARDs. (See "Initial treatment of moderately to severely active rheumatoid arthritis in adults".)
Our approach is generally consistent with other major recommendations or guidelines [13-16]. An alternative approach favored by some experts is the use of methotrexate as the initial DMARD in all patients, unless there are contraindications to its use [14].
Use of DMARDs — For the initial treatment of patients with mildly active RA, particularly those with minimal or low levels of disease activity and especially those who are seronegative, we favor DMARD therapy with HCQ and/or SSZ. We prefer HCQ in patients with relatively less severe disease because this agent is very well-tolerated, is effective, and has a very low risk of significant toxicity. SSZ is used, either by itself or combined with HCQ, in those with relatively more severe disease or adverse prognostic features since it is more effective than monotherapy with HCQ but may be less well-tolerated. Efficacy of treatment of RA with HCQ, as well as SSZ as monotherapy and in combination, is supported by results of randomized clinical trials. (See 'Patients who lack poor prognostic features' below and 'Patients with mild activity and poor prognostic signs' below.)
Alternatively, some rheumatologists favor the use of MTX in this patient subset because of its proven efficacy, long-term durability, and proven effectiveness as co-therapy with added synthetic and biologic DMARDs. (See 'Patients with mild activity and poor prognostic signs' below and "General principles of management of rheumatoid arthritis in adults", section on 'Prognosis'.)
The use of HCQ and/or SSZ in patients with mildly active RA is consistent with the 2008 American College of Rheumatology (ACR) recommendations on the use of DMARDs in RA [13]. The recommendations of the European League Against Rheumatism (EULAR) also note that patients with low disease activity may not require MTX, which they otherwise suggest as the initial DMARD [14]. The EULAR recommendations favor limiting the use of HCQ monotherapy to patients with very mild disease and contraindications to other DMARDs. Our approach is described below for each of the agents used in these patients.
Patients who lack poor prognostic features — We suggest that HCQ be used as the initial DMARD for patients who have mildly active RA and lack poor prognostic features, such as functional limitation, extraarticular disease manifestations, positive rheumatoid factor or anti-CCP antibodies, or bony erosions on radiographs [17]. Such patients have fewer joints involved, as well as less swelling and tenderness. (See "Antimalarial drugs in the treatment of rheumatic disease" and "General principles of management of rheumatoid arthritis in adults", section on 'Prognosis'.)
We also use HCQ in patients with findings limited to mild inflammatory arthritis and a positive antinuclear antibody test, in whom a distinction cannot be made between early RA, undifferentiated immune-inflammatory disease, and early systemic lupus erythematosus. We use HCQ as the initial DMARD because of its very low level of toxicity, although HCQ may be less effective than MTX, SSZ, and other DMARDS. (See 'Patients with mild activity and poor prognostic signs' below.)
Additional benefits of HCQ in patients with RA are the reduced risk of diabetes mellitus associated with use of the drug and its favorable effects on lipids [18,19]. We use HCQ at doses of 200 to 400 mg/day up to 6.5 mg/kg (based upon ideal body weight); other antimalarial drugs may also be of benefit. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular health'.)
HCQ has been compared with placebo in randomized trials in patients with active RA, where it exhibits moderate efficacy in RA compared with placebo and is very well-tolerated [17,20-22]. A 2000 systematic review and meta-analysis of four trials, which involved 592 patients randomized to receive either HCQ or placebo, showed significant benefit from HCQ compared with placebo; various outcome measures including joint counts, pain, and global assessments were assessed (standardized mean differences from placebo ranging from -0.33 to -0.52) [23]. There were no differences between groups in withdrawals for toxicity, but withdrawals for lack of efficacy were significantly less frequent in the HCQ group. In one study, as an example, withdrawals for lack of efficacy at six months were significantly fewer with HCQ compared with placebo (16 versus 34 percent) [17].
Radiographic deterioration was comparable at 12 months in patients randomized to either HCQ or placebo in the one study that examined this question [17].
HCQ is extremely well-tolerated. The adverse effects of HCQ and recommendations for drug monitoring, including baseline and follow-up ophthalmologic evaluation, are discussed in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Monitoring for toxicity'.)
The administration of HCQ commonly results in clinical improvement within two to three months, but maximum effects may require up to four to six months of therapy. In patients who do not respond adequately to HCQ within three months, we add an alternative DMARD, usually MTX, or combine HCQ with other DMARDs, such as SSZ and MTX. (See "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate'.)
Patients with mild activity and poor prognostic signs — Some of us suggest SSZ (gradually titrated up to a dose of 1000 mg two or three times daily) rather than HCQ in patients with mild disease activity but relatively more symptoms and signs of active synovitis or poor prognostic features, such as functional limitation [24]. Some rheumatologists and one of the authors prefer to limit SSZ use to patients lacking poor prognostic features and use MTX in those patients who have poor prognostic signs. (See "General principles of management of rheumatoid arthritis in adults", section on 'Other considerations in RA management' and "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate' and "General principles of management of rheumatoid arthritis in adults", section on 'Prognosis'.)
The relative efficacy of SSZ compared with HCQ was assessed in a randomized controlled trial of 60 patients in which the median number of erosions at 48 weeks was significantly lower with SSZ (5 versus 16) [25]. Although SSZ works more quickly than HCQ and has greater clinical efficacy, it is not as well-tolerated as HCQ [25]. SSZ may be used as monotherapy but is most commonly used in the United States together with other DMARDs, typically in combination with MTX and HCQ.
In a meta-analysis of eight randomized trials, which included 552 subjects who received SSZ and 351 who received placebo, active therapy was significantly more effective than placebo [26]. SSZ, compared with placebo, significantly reduced the duration of morning stiffness (61 versus 33 percent), the number of painful joints (59 versus 33 percent), the number of swollen joints (51 versus 26 percent), and the amount of joint pain (42 versus 15 percent). Whether SSZ alone can retard the rate or prevent the development of erosive disease is less well-established than its clinical benefit. Studies from two major centers found a reduction in the development of new erosions in the first three years of disease in patients receiving SSZ [25,27,28].
Additional trials indicate that SSZ is of comparable efficacy to parenteral gold and of greater efficacy than azathioprine. In trials using lower doses of MTX than have subsequently been employed, SSZ was comparable to both methotrexate (MTX) and leflunomide. The supportive data regarding its efficacy and safety and a more detailed discussion of the use of SSZ in RA are presented in detail elsewhere. (See "Sulfasalazine in the treatment of rheumatoid arthritis".)
Side effects of SSZ may limit its use in some patients. The adverse reactions described for SSZ are either idiosyncratic (eg, hypersensitivity or immune-related), such as skin reactions or hepatitis, or dose-related, such as gastrointestinal upset, headache, leukopenia, or anemia [29]. The idiosyncratic reactions require permanent drug discontinuation, while the dose-related effects may be managed by dose reduction. Approximately 20 to 25 percent of patients withdraw from clinical trials because of intolerable side effects [30]. Two-thirds of such withdrawals result from symptoms due to gastrointestinal and central nervous system toxicity, and approximately 4 to 5 percent because of rash [30]. A complete blood count, serum hepatic aminotransferases, blood urea nitrogen, and creatinine should be obtained every two to four weeks during the first three months of therapy with SSZ. Once safety and tolerability have been established in the initial three months, laboratory testing should be obtained every 8 to 12 weeks; testing after six months of therapy should be performed every 12 weeks [13,24]. (See "Sulfasalazine in the treatment of rheumatoid arthritis", section on 'Adverse effects' and "General principles of management of rheumatoid arthritis in adults".)
In patients who do not respond adequately to SSZ within three months, we use MTX or a comparably effective alternative, or we combine SSZ with other DMARDs, such as HCQ and MTX. (See "Initial treatment of moderately to severely active rheumatoid arthritis in adults".)
Other therapies — We generally do not use minocycline for the treatment of RA in patients able to take other established DMARDs, although it has been used in the past for some patients with mild RA. Minocycline exhibits modest benefit compared with placebo in trials involving patients with longstanding active RA, but greater benefit in rheumatoid factor-positive patients with RA for less than a year [31-34]. It was superior to HCQ in another study of rheumatoid factor-positive patients with early disease [35]. However, minocycline has not been directly compared with SSZ, MTX, or other major DMARDs in common use since the 1990’s, and there are limited data to demonstrate that minocycline prevents the development of bone erosions or otherwise reduces joint injury.
Patients resistant to initial DMARD therapy — The more potent nonbiologic DMARDs, such as MTX and LEF, and the biologic DMARDs, such as the tumor necrosis factor (TNF) inhibitors, are preferred in patients who do not respond adequately, have more active disease, or have poor prognostic markers compared with the patients described above. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy".)
Symptomatic treatment
Antiinflammatory agents — We include an NSAID at full therapeutic dose (eg, naproxen 500 mg twice daily) in the initial treatment of many patients with mildly active RA, unless contraindicated by gastrointestinal (eg, peptic ulcer, gastroesophageal reflux), renal (eg, renal insufficiency), or cardiovascular (eg, uncontrolled hypertension, heart failure) disease. NSAIDs do not prevent the development of erosive disease in patients with continued disease activity, although they can provide clinically important symptomatic relief of pain, stiffness, and swelling. In the occasional patient with mildly active RA in whom NSAIDs are insufficient, we use glucocorticoids as bridging therapy until adequate responses to DMARDs occur. (See 'Use of DMARDs' above.)
Initial symptomatic therapy — The relative efficacy and toxicity of the different NSAIDs vary for individuals. The choice of the initial agent, therefore, depends upon the patient’s history of prior prescription or over-the-counter NSAID use, including the dose taken and his/her tolerance of and previous response to such medications. We titrate the dose of the NSAID to the optimum tolerated level and treat for at least two weeks before making a decision to switch to another NSAID for lack of efficacy, because maximal analgesic and antiinflammatory effects are usually achieved within 10 to 14 days. The use of NSAIDS, especially in older adults, may require simultaneous gastroprotection (eg, with proton pump inhibitors). Increased risk of adverse cardiovascular effects is also a concern with many NSAIDs; thus, the duration of NSAID use should generally be limited once DMARD therapy becomes effective. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "NSAIDs (including aspirin): Treatment of gastroduodenal toxicity" and "Nonselective NSAIDs: Adverse cardiovascular effects" and "COX-2 selective inhibitors: Adverse cardiovascular effects".)
The dose of a given medication required by different patients may vary. Effective total daily antiinflammatory doses include 500 mg twice daily of naproxen, 800 mg three to four times daily of ibuprofen, 200 mg once daily of celecoxib, or a single daily dose of a longer-acting agent, such as 20 mg of piroxicam. Alternatives to the non-salicylate NSAIDs are the non-acetylated salicylates (eg, salsalate, 2000 to 3000 mg/day), which have proven antiinflammatory activity with fewer adverse gastrointestinal effects. (See "NSAIDs: Therapeutic use and variability of response in adults" and "Overview of selective COX-2 inhibitors".)
We continue trials of individual NSAIDs until the patient has achieved adequate control of symptoms with minimal side effects and until effective control of disease activity with DMARD therapy is achieved (ie, decreased swollen joints and acute phase reactants). Treatment with glucocorticoids should be offered as a “bridge therapy” if adequate control of inflammation is not achieved within two weeks; other experts have recommended a two-week trial of another NSAID before resorting to glucocorticoids. We do not combine NSAIDs with each other. Clinical experience suggests that substantially increased risk of gastrointestinal toxicity associated with high-dose NSAID use outweighs the very limited benefit (if any) that may occur when using more than one agent. (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity".)
Inadequate response to NSAIDs — Systemic glucocorticoids, such as oral prednisone or prednisolone, are needed infrequently in patients with early, mildly active RA. We use glucocorticoids in such patients if disease is not well-controlled with a combination of NSAIDs and a DMARD. We suggest starting with 5 to 15 mg/day of prednisone or equivalent, depending upon the severity of the inflammation and comorbidities, to ameliorate symptoms and then tapering to a lower dose as tolerated (preferably no more than 7.5 mg/day of prednisone) to maintain control temporarily while DMARDs begin to take effect. In general, this will permit reduction and discontinuation of the glucocorticoids within four to six months. Alternatively, methylprednisolone acetate (120 mg administered intramuscularly) is used by some rheumatologists as “bridge therapy,” which may be repeated at four and eight weeks if DMARDs have not controlled symptoms [36]. Further information regarding the benefits and hazards of various doses of glucocorticoids, their route of administration, and long-term use can be found elsewhere. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'Glucocorticoids'.)
Intraarticular injections of long-acting glucocorticoids (eg, triamcinolone hexacetonide) are used to reduce synovitis in particular joints that are more inflamed than others. A single active joint out of proportion to others in RA should always raise concern about infection, which may be difficult to distinguish from RA alone. Thus, if infection is a consideration, joint fluid should be obtained to exclude infection. (See "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?" and "Septic arthritis in adults", section on 'Rheumatoid arthritis'.)
Analgesics — In addition to the medications noted above, we use analgesic medications, such as acetaminophen and/ortramadol, for additional pain relief if required. We avoid the use of opioids in patients with mildly active RA because their pain can be controlled by effective use of antiinflammatories and DMARDs that control the disease process. Patients who appear to require opioids for adequate pain relief should be evaluated for fibromyalgia or other comorbid causes of pain (eg, fracture, tumor, spinal disorders, or others).
MONITORING AND REEVALUATION — During the initial treatment of patients with mildly active rheumatoid arthritis (RA), the patient should be reevaluated every four to eight weeks, depending upon several variables. These include the extent to which symptoms are controlled by treatment, whether adjustments or changes are required in the medication regimen, and the need to monitor for possible drug toxicity [24,37,38]. We advise the periodic reevaluation of disease activity using a quantitative composite measure at each assessment (eg, Disease Activity Score in 28 joints [DAS28] or Clinical Disease Activity Index [CDAI]). These visits also provide an opportunity for patient education and other interventions noted above. The composite measures and their use, direct links to calculators for these measures, and the approach to monitoring of patients being treated for RA are presented in detail elsewhere. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice".)
In patients who fail to achieve remission or very low disease activity within three months of initiating therapy or who require more than 5 mg/day of prednisone or equivalent glucocorticoid to maintain a state of remission, we suggest use of a more potent disease-modifying antirheumatic drug (DMARD) (eg, methotrexate [MTX]) or a combination of DMARDs. (See "Initial treatment of moderately to severely active rheumatoid arthritis in adults".)
DRUG THERAPY FOR FLARES — Rheumatoid arthritis (RA) has natural exacerbations (also known as flares) and reductions of continuing disease activity. It is important to distinguish a disease flare, characterized by symptoms and physical and laboratory findings of increased inflammatory synovitis, from noninflammatory causes of local or generalized increased pain. The severity of the flare and background drug therapy influence the choice of therapies. Drug therapy for flares is discussed in greater detail elsewhere. (See "Clinical manifestations of rheumatoid arthritis".)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topic (see "Patient information: Disease modifying antirheumatic drugs (DMARDs) (The Basics)")
●Beyond the Basics topics (see "Patient information: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient information: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient information: Disease-modifying antirheumatic drugs (DMARDs) (Beyond the Basics)" and "Patient information: Complementary and alternative therapies for rheumatoid arthritis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Patients with mildly active rheumatoid arthritis (RA) typically have fewer than five inflamed joints, no extraarticular disease, negative rheumatoid factor and/or anti-cyclic citrullinated peptide (CCP) antibody testing, and no evidence of erosions or cartilage loss on plain radiographs. We recommend that all patients with the diagnosis of RA, including patients with mild disease, be treated with a disease-modifying antirheumatic drug (DMARD) (Grade 1B). Additional principles for the treatment of RA include achieving and maintaining tight control of disease activity, with the ideal goal of remission; the use of antiinflammatory agents, including glucocorticoids, only as adjunctive agents; and the participation of a rheumatologist in the evaluation and ongoing care of the patient. (See 'Definition of mildly active RA' above and 'General principles' above and "General principles of management of rheumatoid arthritis in adults", section on 'Early use of DMARDs'.)
●Patient education and other nonpharmacologic and preventive therapies are needed for all patients with RA. (See 'Nonpharmacologic and preventive therapies' above and "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis".)
●In patients with mildly active RA, particularly those without poor prognostic features or with findings limited to mild inflammatory arthritis and a positive antinuclear antibody test (in whom a distinction cannot be made between early RA and early systemic lupus erythematosus), we suggest that an antimalarial drug, preferably hydroxychloroquine (HCQ), be used rather than sulfasalazine (SSZ) or methotrexate (MTX) as the initial DMARD (Grade 2B). (See 'Patients who lack poor prognostic features' above.)
●In patients with mildly active RA with more symptoms and signs of active synovitis, functional limitation, or positive testing for rheumatoid factor or anti-CCP antibodies, we suggest SSZ rather than an antimalarial drug (Grade 2B). An alternative approach preferred by some experts and one of the authors is to initiate treatment with MTX in such patients. (See 'Patients with mild activity and poor prognostic signs' above.)
●We use antiinflammatory drug therapy in addition to DMARDs, including nonsteroidal antiinflammatory drugs (NSAIDs), or glucocorticoids on a temporary basis to quickly achieve control of signs and symptoms of disease, and we then taper and withdraw these medications once DMARDs have taken effect. Intraarticular injections of long-acting glucocorticoids are used to reduce synovitis in particular joints that are more inflamed than others. When clinically indicated, joint fluid should be obtained to exclude infection. (See 'Antiinflammatory agents' above and 'Initial symptomatic therapy' above and 'Inadequate response to NSAIDs' above.)
●During the initial treatment of patients with mildly active RA, the patient should be reevaluated every four to eight weeks to assess the effectiveness of therapy and to monitor for possible drug toxicity. We advise the periodic reevaluation of disease activity using a quantitative composite measure at each assessment. In patients who fail to achieve remission within three months of initiating therapy or who require more than 5 mg/day of prednisone or equivalent glucocorticoid to maintain a state of remission, we suggest a more potent DMARD or combination of DMARDs (Grade 2C). (See 'Monitoring and reevaluation' above and "Initial treatment of moderately to severely active rheumatoid arthritis in adults".)