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Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults

Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults
Literature review current through: Sep 2023.
This topic last updated: Feb 23, 2022.

INTRODUCTION — The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis and the prevention of joint damage, which begins early in the course of disease and may ultimately result in disability. Patients are less likely to respond well to therapy the longer active disease persists, and it is widely accepted that patients with active RA should be treated with disease-modifying antirheumatic drugs (DMARDs) at the earliest stage of disease, ideally within less than three months of symptom onset. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Prognosis' and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Early use of DMARDs'.)

The most commonly used DMARD for the initial treatment of RA is methotrexate (MTX), although some patients are unable or reluctant to take this drug, and alternative agents are sometimes necessary as the initial DMARD in place of MTX. The choice of therapeutic agents, including both antiinflammatories and DMARDs, is influenced by multiple factors. (See 'Approach to management' below and "Initial treatment of rheumatoid arthritis in adults".)

The alternatives to MTX as the initial DMARD for the treatment of patients with active RA will be reviewed here. A more comprehensive description of the general principles of RA management and the initial treatment of RA, as well as the diagnosis and differential diagnosis of RA and the treatment of disease resistant to initial therapy, are presented separately. (See "General principles and overview of management of rheumatoid arthritis in adults" and "Initial treatment of rheumatoid arthritis in adults" and "Diagnosis and differential diagnosis of rheumatoid arthritis" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

APPROACH TO MANAGEMENT — Alternatives to methotrexate (MTX) are sometimes used for the initial treatment of rheumatoid arthritis (RA) either because of comorbidities that present an absolute or relative contraindication to MTX, the initial disease-modifying antirheumatic drug (DMARD) usually employed for treating RA, or because of patient or clinician preferences. (See "Initial treatment of rheumatoid arthritis in adults".)

The choice of the alternative agent to MTX is largely based upon the following: disease severity; comorbidities; patient preferences regarding relative risks and benefits and route of administration; and regulatory, insurance, and cost limitations. It is further shaped by evidence from indirect comparisons and limited head-to-head comparisons. (See 'Assessment of disease activity and prognosis' below and 'Other management issues' below and 'Choice of therapy' below.)

Most patients unable to take MTX can be treated initially with another nonbiologic conventional synthetic DMARD (csDMARD), such as leflunomide (LEF). Alternative nonbiologic DMARDs, depending upon comorbidities, prognostic features, and other factors, include sulfasalazine (SSZ), hydroxychloroquine (HCQ), and other much less frequently used agents. The use of HCQ monotherapy is typically limited to patients with very mild or limited disease.

In patients unable to use these medications, a biologic agent such as a tumor necrosis factor (TNF) inhibitor is typically preferred, but several other biologic agents can be used for initial monotherapy. Other potential treatment options include kinase inhibitors, which have been classified as targeted synthetic DMARDs (tsDMARDs).

GENERAL PRINCIPLES — There are several general principles that are important in the management of all patients with rheumatoid arthritis (RA), regardless of the specific drugs chosen to treat the disease. These principles are discussed in detail separately. (See "General principles and overview of management of rheumatoid arthritis in adults".)

Briefly, these include:

Evaluation and ongoing care by a rheumatologist

Treatment of all patients diagnosed with RA with disease-modifying antirheumatic drug (DMARD) therapy to prevent, arrest, or retard disease-related damage

Achievement and maintenance of tight control of disease activity, defined as remission or a state of minimal disease activity, without compromising of safety

Use of antiinflammatory therapies, including nonsteroidal antiinflammatory drugs (NSAIDs) and glucocorticoids, to help control symptoms until DMARDs take effect

Identification, management, and prevention of comorbid conditions that can complicate the disease course

Our approach is generally consistent with the recommendations of major groups, such as the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) [1,2].

ASSESSMENT OF DISEASE ACTIVITY AND PROGNOSIS — Patients should be assessed for their level of disease activity as a major element in determining drug choice. Adverse prognostic features should also be noted but are of less importance than disease activity in treatment choices.

Disease activity is best assessed by use of a quantitative composite measure, 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)-3 [3,4]. Adaptations of such measures for use in telehealth visits have also been proposed [5]. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Assessment and monitoring' and "Assessment of rheumatoid arthritis disease activity and physical function" and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Overview of assessment and monitoring'.)

Important elements of the patient assessment include physical function, pain, the number of tender and swollen (ie, inflamed) joints, and extraarticular disease. We also find that the Health Assessment Questionnaire (HAQ)-II is a useful measure in clinical practice for routine assessment of functional status at each patient visit; a commonly used alternative measure is the Multidimensional HAQ (MD-HAQ) [6,7]. Laboratory indices of inflammation, including the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, may also be assessed. (See 'Monitoring and reevaluation' below.)

Another measure that has been advocated for the assessment of disease activity is a blood test, the proprietary multibiomarker disease activity (MBDA) test, although there is a lack of evidence to support its additional value over standard clinical measures of disease activity as part of routine care [4]. (See "Biologic markers in the assessment of rheumatoid arthritis", section on 'Multi-protein biomarker algorithms'.)

Compared with the level of disease activity, the presence or absence of features historically predicting a poor prognosis has limited influence on treatment decisions, particularly given the efficacy and relative safety of current treatment approaches, together with the wide acceptance of the importance of starting DMARDs early in all patients with rheumatoid arthritis (RA) (see "General principles and overview of management of rheumatoid arthritis in adults", section on 'Early use of DMARDs'). Those features predicting a poor prognosis include rheumatoid factor (RF) and anti-citrullinated protein antibodies, functional limitation, extraarticular disease, and the presence of bone erosions on radiographs. The prognosis of RA is discussed in more detail separately. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Prognosis'.)

OTHER MANAGEMENT ISSUES — Other management issues, in addition to the choice of disease-modifying antirheumatic drug (DMARD) therapy, are of critical importance in the comprehensive care of patients with rheumatoid arthritis (RA). These issues are addressed in detail separately; briefly, they include:

Nonpharmacologic and preventive therapies – A number of nonpharmacologic measures and other medical interventions are important in the comprehensive management of RA, in addition to antiinflammatory and antirheumatic drug therapies. These interventions, including patient education, vaccinations, cardiovascular and fracture risk reduction, and others, are discussed in detail elsewhere. (See "Nonpharmacologic therapies for patients with rheumatoid arthritis" and "Immunizations in autoimmune inflammatory rheumatic disease in adults".)

Pretreatment interventions – We take a number of important precautions before using DMARDs, including laboratory assessments (complete blood count, serum creatinine, aminotransferases, and other studies as indicated), evaluation of comorbidities, vaccinations, and screening for hepatitis C, hepatitis B, and latent tuberculosis infection. Many rheumatologists obtain a baseline chest radiograph for later comparison if pulmonary issues arise. These issues are discussed in detail elsewhere. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults" and "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors" and "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection" and "Overview of pleuropulmonary diseases associated with rheumatoid arthritis" and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

Antiinflammatory symptom management – We use nonsteroidal antiinflammatory drugs (NSAIDs) and/or glucocorticoids (systemic and/or intraarticular) for initial symptomatic control of inflammation while awaiting the response to DMARD therapy. We do not use NSAIDs or glucocorticoids as the sole or primary treatments. The use of these medications, including NSAIDs and oral and intraarticular glucocorticoids, is discussed in detail separately. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Symptomatic treatment with antiinflammatory drugs'.)

Analgesic (non-antiinflammatory) agents – In addition to the medications noted above, we use analgesic medications, such as acetaminophen and/or low doses of tramadol, if required, for additional pain relief. We avoid the use of stronger opioid analgesics when possible in patients with RA because their pain can typically 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 other comorbid causes of pain (eg, fracture, tumor, spinal disorders, fibromyalgia, or others).

Drug therapy for flares – 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 other causes of joint inflammation (eg, septic arthritis), as well as 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 "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug therapy for flares'.)

INITIAL TREATMENT CHOICES

Choice of therapy — In most patients who require an alternative to methotrexate (MTX), we generally use monotherapy with leflunomide (LEF) or sulfasalazine (SSZ). For patients whose drug choice is not limited by regulatory or insurance restrictions, a tumor necrosis factor (TNF) inhibitor (eg, etanercept or adalimumab), abatacept, or tocilizumab are appropriate options, given the available evidence from randomized trials. Patients with low disease activity may respond to hydroxychloroquine (HCQ) alone, or to SSZ. (See 'Nonbiologic traditional DMARD alternatives to methotrexate' below and 'Tumor necrosis factor inhibitors' below and 'Other alternative agents' below.)

There are insufficient data to determine the optimal initial therapy in patients who require an alternative to MTX. The use of these agents as alternatives when MTX cannot be used is supported by trials comparing biologic or other nonbiologic disease-modifying antirheumatic drugs (DMARDs) to MTX, which have demonstrated largely similar or occasionally better efficacy of these other agents, although MTX dosing and route of administration have often not been fully optimized in these trials. In particular, the trials have not evaluated split oral dosing for MTX doses above 15 mg/week, where bioavailability is quite variable between individual patients; nor have they evaluated parenteral administration of higher MTX doses, which can enhance efficacy and tolerability. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Alternatives to once-weekly oral therapy'.)

There are insufficient direct comparisons of the various non-MTX conventional synthetic DMARDs (csDMARDs) in early rheumatoid arthritis (RA) with each other to recommend one specific non-MTX csDMARD over other DMARDs for all patients in this situation. Thus, the choice of agent is largely based upon a combination of factors, including regulatory or insurance requirements, comorbidities and patient preferences regarding relative risks and benefits, route of administration, and cost. (See 'Tumor necrosis factor inhibitors' below and 'Other alternative agents' below.)

Several trials have shown greater benefit with Janus kinase (JAK) inhibitors than MTX in early RA when they have been directly compared, providing evidence of efficacy in this setting (see 'JAK inhibitors' below and 'Tofacitinib' below and 'Baricitinib' below and 'Upadacitinib' below and 'Filgotinib' below). However, safety concerns from a phase 3b/4 clinical trial demonstrating a dose-dependent increased risk in major adverse cardiovascular events (MACE), malignancy, opportunistic infection, venous thromboembolisms (VTEs), and overall mortality with tofacitinib compared with TNF inhibitors in RA patients with cardiovascular risk factors resulted in the US Food and Drug Administration (FDA)-recommending JAK inhibitor utilization only after TNF inhibitor failure so this is no longer an appropriate option for most patients [8]. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Pretreatment screening and precautions' and "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Adverse effects'.)

We take the following general approach:

In most patients with active RA who are unable to use MTX, we suggest an alternative oral csDMARD such as LEF, and less often SSZ, rather than a biologic agent, as initial DMARD therapy. These drugs are taken orally and have a lower risk of serious adverse effects, including infection, than the TNF inhibitors, other biologic DMARDs, and the JAK inhibitors. (See 'Nonbiologic traditional DMARD alternatives to methotrexate' below and 'Tumor necrosis factor inhibitors' below and 'Other alternative agents' below.)

In patients with moderate to severely active disease or significant functional impairment who are not restricted by regulatory or cost constraints, a TNF inhibitor is a reasonable alternative as the initial agent rather than a csDMARD because of the efficacy and relative rapidity of onset of these drugs. Among the available agents, etanercept is our first choice, followed by adalimumab. A TNF inhibitor would also be preferred in patients in whom LEF should be avoided because of contraindications to its use (eg, patients with untreated hepatitis C or who are planning pregnancy). (See 'Tumor necrosis factor inhibitors' below.)

Additional alternatives are abatacept and tocilizumab, biologic DMARDs usually administered by subcutaneous injection but available by intravenous infusion. Abatacept monotherapy has been shown to yield similar efficacy and safety to MTX (see 'Abatacept' below). Tocilizumab was found more effective than MTX monotherapy in a trial in early RA (see 'Tocilizumab' below). Patient preference regarding route of administration, regulatory and cost constraints, and clinician experience with these agents are the major factors usually determining choice in a given patient.

In patients with few tender or swollen joints, particularly among those who lack adverse prognostic signs (eg, seronegative RA without evidence of erosions), we usually use HCQ as the initial alternative DMARD to MTX. (See 'Limited arthritis' below.)

In the infrequent patients unable to use any of the preferred options as the initial DMARD, other alternative agents may be of benefit. (See 'Other alternative agents' below and 'Special populations' below.)

Randomized trials have demonstrated the benefit of each agent compared with placebo, and the efficacy of these agents has also been documented in head-to-head comparisons, including of MTX with TNF inhibitors (see 'Tumor necrosis factor inhibitors' below); MTX with tocilizumab [9]; abatacept with MTX [10]; and MTX, LEF, and SSZ with each other. (See 'Leflunomide' below and 'Sulfasalazine' below.)

Nonbiologic traditional DMARD alternatives to methotrexate — In most patients with RA who require an alternative to MTX, we suggest LEF for initial therapy rather than SSZ, while SSZ is an alternative for some patients, particularly those with only low to low-to-moderate disease activity (see 'Leflunomide' below and 'Sulfasalazine' below). HCQ can be used in some patients with less severe disease. (See 'Limited arthritis' below.)

Leflunomide — We suggest LEF (20 mg once daily) in most patients with active RA who are unable to use MTX as their initial DMARD. LEF can also be used for patients unable to use MTX in whom a TNF inhibitor may be preferred, but who are unable to use a biologic DMARD for initial therapy due to regulatory, insurance, or cost limitations. We may also use LEF in patients who have a strong preference for an oral rather than a parenteral agent. In patients unable to use MTX because of liver disease and in women planning pregnancy, LEF should be avoided and an alternative such as SSZ may be appropriate. The use and safety of LEF are discussed in detail separately. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis".)

Among nonbiologic DMARDs, we prefer LEF over SSZ because of its potentially greater efficacy, especially for the treatment of moderate to severely active RA, regardless of the presence or absence of poor prognostic factors [11-13]. Some randomized trials suggest that LEF is more effective than SSZ in achieving a clinical response, decreasing functional disability, and reducing progression of erosive changes [14-17]; others indicate comparable efficacy of the two agents [18,19]. Additionally, the adverse effect profile of LEF is generally similar to that of MTX, with similar rates of withdrawal for drug toxicity at two years [18,20]. The drug should be avoided in patients with chronic liver disease but may be used in patients with mild to moderate renal dysfunction in whom it is safer than MTX. Women of childbearing potential must be on adequate contraception and go through LEF washout prior to pursuing pregnancy.

The efficacy of LEF was comparable with MTX and superior to placebo in a meta-analysis and in randomized trials comparing these agents, but these trials have been criticized for using lower maximum doses of MTX (up to 15 mg/week) than have subsequently been commonly employed (up to 25 mg/week) [21-24]. As an example, in one trial involving 482 MTX-naïve patients, an American College of Rheumatology (ACR) criteria for 20 percent improvement (ACR20) at one year was achieved in a similar proportion of patients on LEF or on MTX, and this rate was significantly higher than that seen with placebo (52 and 46 percent versus 26 percent) [22]. LEF has not been directly compared with the TNF inhibitors, but the superiority of TNF inhibitors is suggested by several observations; these include the comparability of LEF to SSZ and to sometimes suboptimal doses of MTX, the more rapid effects and greater overall benefit of TNF inhibitors when they have been directly compared with MTX or SSZ, and clinical experience. Additional data describing the efficacy of LEF, particularly in patients resistant to initial DMARD therapy, are described separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Leflunomide'.)

Sulfasalazine — We prefer to limit the use of SSZ as an alternative for MTX to patients with a strong preference for an oral agent and in whom LEF is contraindicated, such as patients with liver disease or women planning pregnancy. SSZ can also be used as an alternative to HCQ in patients with more limited disease. SSZ alone (begun at 500 mg twice daily and gradually increased [eg, by 500 mg per week] to up to 3000 mg daily divided into two or three doses) or in combination with HCQ was effective in trials including patients with early, severely active RA [11,13]. The use of SSZ in this group is also consistent with the recommendations of the ACR [11,25]. A trial of SSZ can also be used regardless of the presence of adverse prognostic features if needed, particularly in patients with low to low-to-moderate disease activity.

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/or HCQ (see "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'DMARD triple therapy'). The efficacy of SSZ monotherapy in the treatment of RA has been evaluated and documented in numerous randomized trials [17,26-35]. In at least one randomized trial, the combination of SSZ and HCQ demonstrated efficacy that was similar to that of MTX monotherapy, suggesting that this combination may also be a reasonable alternative therapeutic combination in patients unable to take MTX [36].

SSZ, rather than HCQ alone, should be used, either by itself or combined with HCQ, in those with relatively more severe disease because it is more effective than monotherapy with HCQ [33], although it may be less well tolerated.

In a meta-analysis of eight randomized trials involving 903 patients, active therapy with SSZ was significantly more effective than placebo [30]. SSZ, compared with placebo, was more likely to significantly reduce 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 but has also been examined [17,32-35]. 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, compared with placebo and with HCQ [32,33,37]. As an example, the relative efficacy of SSZ was compared with HCQ in a randomized trial involving 60 patients with RA; the median number of erosions at 48 weeks was significantly lower with SSZ (5 versus 16) [33]. Although SSZ works more quickly than HCQ and has greater clinical efficacy, it is not as well tolerated as HCQ [33]. Another trial showed a statistically significantly lower eroded joint count and slower radiographic disease progression with SSZ compared with placebo, and similar benefit to LEF [17].

Additional trials indicate that SSZ is of comparable efficacy to parenteral gold and of greater efficacy than azathioprine (see 'Other alternative agents' below). In trials using lower doses of MTX than have subsequently been employed, SSZ was comparable to both MTX and LEF, although persistence on therapy over 24 months was poor. A number of trials comparing SSZ with the various nonbiologic (conventional) DMARDs have been performed [38-42], including comparisons with MTX [43,44].

Treatment adherence with SSZ regimens can be more difficult than with other DMARDs, given the need for two to three times daily administration of a total of four to six pills, as well as the occurrence of side effects, which may also limit its use in some patients [45,46].

The adverse reactions described for SSZ are either idiosyncratic (eg, hypersensitivity or immune-related), such as skin reactions, agranulocytosis (eg, acute neutropenia), or hepatitis; or dose-related, such as gastrointestinal upset, headache, leukopenia, or anemia [47]. 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 [38]. Two-thirds of such withdrawals result from symptoms due to gastrointestinal and central nervous system toxicity (including headache), and approximately 4 to 5 percent because of rash [38]. The adverse effects of SSZ are discussed in more detail elsewhere. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis", section on 'Adverse effects' and "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis", section on 'Desensitization'.)

A complete blood count, serum hepatic aminotransferases, 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 [11,48]. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis", section on 'Adverse effects' and "General principles and overview of management of rheumatoid arthritis in adults".)

Discontinuation of SSZ due to toxicities may be required, with one study demonstrating that 30 and 50 percent of patients stopped treatment due to adverse effects over two and five years of follow up, respectively [49]. Other studies suggest rates that are similar to those of LEF and MTX [18].

In patients who do not respond adequately to SSZ within three months, another DMARD or DMARD combination should be used. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

Tumor necrosis factor inhibitors — A number of biologic DMARDs, particularly the TNF-alpha inhibitors, have been proven effective as monotherapy, compared with placebo or MTX, in randomized trials in patients with moderate and severely active RA, including patients who were naïve to MTX and other DMARDs [50-52]. Few head-to-head comparisons of anti-TNF agents as monotherapy have been performed in DMARD-naïve patients; trials in combination with MTX have been done in patients with an inadequate MTX response (showing comparability of certolizumab and adalimumab) [53], but results from indirect analyses are available [54]. These agents are often preferred in patients with moderate to high disease activity, particularly when nonbiologic alternatives such as LEF are contraindicated. We generally use TNF inhibitors in this setting rather than other biologic alternatives or JAK inhibitors based upon their known efficacy in this setting and longer-term experience with these agents. TNF inhibitors that we use as initial therapy in this setting include:

Etanercept – Etanercept has shown generally similar or modestly greater efficacy compared with MTX in randomized trials, including a randomized trial in patients with early RA, naïve to MTX, in which it resulted in more rapid and greater improvement and reduced joint damage compared with MTX [50,55]. There is slightly longer experience with this agent, and there is indirect evidence of lower rates of serious infections compared with other biologic DMARDs, including adalimumab and infliximab [50,54]. In our experience, benefit is also reached more quickly with etanercept and other TNF inhibitors than with most nonbiologic DMARDs, including MTX, LEF, HCQ, and SSZ.

Adalimumab – Adalimumab is also effective in this group of patients; it is administered as an every-other-week injection [50,51]. The use of adalimumab is supported by randomized trials showing comparable clinical efficacy but greater inhibition of radiographic progression compared with MTX as initial DMARD monotherapy [51], and by indirect comparisons in a meta-analysis of randomized trials showing comparable efficacy to other TNF inhibitors [54].

The newer TNF inhibitors, certolizumab pegol and golimumab, are also effective as monotherapy and therefore represent reasonable alternatives to etanercept and adalimumab. Certolizumab may have advantages over the other TNF inhibitors during pregnancy, with respect to evidence demonstrating negligible fetal drug exposure throughout pregnancy. Golimumab was comparably effective to MTX in a randomized trial of MTX-naïve patients [56]. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Tumor necrosis factor inhibitors' and "Rheumatoid arthritis and pregnancy", section on 'During pregnancy'.)

Use of infliximab as monotherapy is generally not recommended due to the increased likelihood of developing neutralizing human antichimeric antibodies (HACA) when this chimeric monoclonal antibody is given without other immunosuppressive drugs. However, we recognize that in clinical practice, some patients receive infliximab alone. Loss of efficacy due to emergence of HACA may be overcome by use of increasing doses or preferably by increasing the frequency of administration of infliximab. In addition to added safety concerns with higher cumulative doses, the increased cost associated with this approach may be prohibitive. Biosimilar infliximab may be an alternative that is associated with significantly less expense outside the United States and moderately less expense in the United States. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Infliximab-induced human antichimeric antibodies'.)

Adverse effects of TNF inhibitors are discussed in detail separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects" and "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases" and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy" and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors".)

Additional data describing the efficacy of TNF inhibitors in RA, particularly in patients who were resistant to initial DMARD therapy, are described elsewhere. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

Other alternative agents — Additional agents have been compared with MTX as initial therapy, including abatacept, which inhibits T cell activation, the anti-interleukin 6 (IL-6) receptor antibody tocilizumab, and the JAK inhibitors. Azathioprine is another potential alternative, although little data exist directly comparing this agent with MTX in RA. However, we generally do not use these drugs for initial DMARD therapy given concerns regarding potential toxicities, costs, and regulatory limitations to their use in this context and a lack of long-term evidence for any advantage over other therapies when a treat-to-target approach is employed. These drugs have been compared with MTX in DMARD-naïve patients in a small number of trials.

Abatacept — Abatacept, which inhibits T cell activation, has been compared with MTX monotherapy over a 12-month treatment period as part of a single randomized trial involving 351 patients with early RA [10]. In this trial of RA patients with <2 years disease duration, a similar proportion of patients receiving abatacept monotherapy (125 mg weekly administered subcutaneously) and MTX monotherapy (15 to 20 mg once weekly in most patients) achieved clinical remission (Disease Activity Score in 28 joints and the C-reactive protein [DAS28-CRP] <2.6 in 43 and 45 percent, respectively). The treatments demonstrated similar safety profiles. In another trial in patients with early RA and erosive joint changes the combination of abatacept with MTX was superior to MTX alone, but without added safety concerns [57,58].

The use, efficacy, and safety of abatacept, particularly in patients resistant to initial DMARD therapy, is discussed in detail separately (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus abatacept' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Abatacept'.)

Anti-IL-6 receptor — There are two commercially available antibodies that block the IL-6 receptor, tocilizumab and sarilumab. The former has been more widely used and has been evaluated in patients naïve to DMARD therapy, while the latter agent has not, but in our experience has similar properties to tocilizumab and can be used similarly. (See 'Tocilizumab' below and 'Sarilumab' below.)

Tocilizumab — Two trials illustrate the efficacy of the anti-IL-6 receptor antibody tocilizumab compared with MTX:

Tocilizumab (8 mg/kg administered by intravenous infusion every four weeks either at baseline or after treatment with placebo for eight weeks) was compared with MTX (titrated from 7.5 up to 20 mg/week within eight weeks) in a randomized trial involving 673 patients with active RA for whom previous treatment with MTX or biologic agents had not failed [9]. Approximately one-third of the patients had previously received MTX; less than 10 percent had received a TNF inhibitor in the past. The patients who received tocilizumab were significantly more likely at week 24 to achieve an ACR20 (70 versus 53 percent) or clinical remission (Disease Activity Score in 28 joints [DAS28] <2.6, 34 versus 12 percent). The frequencies of serious adverse events and serious infections were similar between the tocilizumab- and MTX-treated groups, although more patients on tocilizumab experienced a reversible neutropenia (3.1 versus 0.4 percent) and an increased incidence of total cholesterol greater than 240 mg/dL (6.2 mmol/L; 13.2 versus 0.4 percent).

Tocilizumab was more effective than MTX as initial DMARD therapy in a two-year randomized trial involving 317 DMARD-naïve patients with recent-onset RA using a treat-to-target strategy, although the trial had some limitations [59]. Patients underwent monthly clinical assessments including calculation of a quantitative composite measure, the DAS28 and the erythrocyte sedimentation rate (DAS28-ESR). Patients treated with tocilizumab (8 mg/kg intravenously every four weeks) plus MTX and those treated with tocilizumab alone were both significantly more likely compared with patients given MTX alone to achieve a sustained (at least 24 weeks' duration) remission on the initial trial regimens (86 and 84 versus 44 percent; relative risk [RR] 2.00, 95% CI 1.59-2.51, for tocilizumab plus MTX versus MTX; and RR 1.86, 95% CI 1.48-2.32, for tocilizumab versus MTX). MTX was escalated in each regimen every four weeks to a maximum of 30 mg once weekly until achieving remission or until limited by intolerance; the mean MTX doses at week 24 for patients on tocilizumab plus MTX and for those on MTX alone were 11 and 22 mg once weekly, respectively.

Patients not achieving remission on the initial monotherapy regimens were switched from placebo to active therapies, including combination therapy, sometimes including TNF inhibitors, using a defined protocol. For the entire trial period, the outcomes (based upon initial drug allocation to tocilizumab plus MTX, tocilizumab alone, or MTX alone) were similar (sustained remission in 86 versus 88 versus 77 percent); the difference for only the tocilizumab versus MTX comparison was statistically significant (RR 1.14, 95% CI 1.01-1.29). Serious adverse events occurred in 16, 18, and 12 percent of patients in the respective groups. Multiple secondary trial endpoints were analyzed.

A consequence of the trial design, which potentially may have favored the tocilizumab trial arms, was that the dose escalation protocol for patients receiving MTX was suboptimal, without parenteral therapy being used, and the initial added therapy in patients with an inadequate response was three months of HCQ, rather than more intensive therapy, such as a biologic agent or triple therapy with MTX, HCQ, and SSZ.

The use and safety of tocilizumab, particularly after an inadequate response to initial DMARD therapies, are described in more detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tocilizumab'.)

Sarilumab — The use, efficacy, and safety of sarilumab, particularly after an inadequate response to initial DMARD therapy, is discussed in detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus IL-6 inhibitor/IL-6 inhibitor monotherapy' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Sarilumab'.)

JAK inhibitors — Five Janus kinase (JAK) inhibitors are available in multiple countries for clinical use, although one is not available in the United States. These drugs are taken orally, but their availability for patients who are naïve to DMARD therapy is limited by cost and regulatory restrictions. Four of these agents, tofacitinib, baricitinib, upadacitinib, and filgotinib, have been evaluated in patients who are naïve to DMARD therapy (see 'Tofacitinib' below and 'Baricitinib' below and 'Upadacitinib' below and 'Filgotinib' below). Another agent, peficitinib, which is available in Japan, has not been studied in this population. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Upadacitinib' and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Peficitinib' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Upadacitinib'.)

Tofacitinib — Tofacitinib is taken orally as 5 mg twice daily or in an extended-release form of 11 mg taken once daily, and is effective as monotherapy in RA. Tofacitinib (5 or 10 mg taken orally twice daily) was compared with MTX (initially 10 mg taken orally once weekly, increased by 5 mg every four weeks as tolerated to 20 mg orally once weekly) in a randomized trial involving 958 patients with moderate to severely active RA who had not previously received MTX or therapeutic doses of MTX [60]. The patients who received tofacitinib were significantly more likely to achieve ACR20 and ACR70 after six months (71 and 76 versus 51 percent and 26 and 38 versus 12 percent, respectively). Clinical benefit was largely sustained after 24 months (ACR20 of 64 and 64 versus 42 percent and ACR70 of 34 and 38 versus 15 percent). Tofacitinib therapy also resulted in a small but statistically significant reduction in modified total Sharp scores (mTSS) of radiographic change from baseline to six months compared with MTX (mTSS change of 0.2 and <0.1 versus 0.8 points). The radiographic benefit was maintained after 24 months (increase in mTSS of 0.6 and 0.3 versus 2.1 points).

The proportion of patients with serious adverse events was comparable between tofacitinib and MTX (approximately 11 to 12 percent), as was the frequency of patients with serious infection (2 to 3 percent), although herpes zoster developed in 4 percent of patients receiving tofacitinib and in 1 percent of those receiving MTX (underscoring the potential importance of zoster vaccination prior to initiation of this agent). Tofacitinib resulted in greater increases in low- and high-density lipoprotein and serum creatinine compared with MTX and greater reductions in absolute neutrophil and lymphocyte counts.

Although tofacitinib appears effective in this setting, the FDA has supported its use in RA only in adults who have had an inadequate response to, or are intolerant of, MTX. The use, efficacy (particularly in patients resistant to initial DMARD therapy), and safety of tofacitinib are described in more detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Tofacitinib' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Tofacitinib'.)

Baricitinib — Baricitinib is a small-molecule, orally administered, JAK-1 and -2 inhibitor. It is commercially available for use in both Europe (at a dose of either 2 or 4 mg daily) and the United States, although only the lower dose received FDA approval, and the FDA supports its use in RA only in patients who have had an inadequate response to one or more TNF antagonist therapies. It has been effective in patients with RA compared with both placebo and with other active DMARDs and in studies with patients who are naïve to DMARD therapy as well as patients with inadequate responses to prior therapies [61-66].

In patients with active RA who were naïve (or had minimal exposure) to both conventional nonbiologic DMARDs and biologic DMARDs, a randomized trial involving 588 patients found that baricitinib (4 mg daily taken orally) monotherapy was superior to MTX alone in the proportion of patients achieving an ACR20 response at week 24 (77 versus 62 percent) [61]. Greater improvement in disease activity and physical function for patients receiving baricitinib (alone or with MTX) was seen compared with MTX alone as early as week 1. Clinical improvement with the combination of baricitinib and MTX was similar to baricitinib alone, although a statistically significant reduction in radiographic progression compared with MTX alone was seen only with the combination, despite a trend towards such improvement with baricitinib alone. Safety was similar in the three groups, but treatment-emergent adverse events, including infections, appeared to be increased in patients receiving the combination therapy, although the number of events were too few for statistical analysis.

Baricitinib was associated in the trials with minor increases in serum creatinine and in low-density lipoprotein (LDL) cholesterol, and with small reductions in blood neutrophil counts. As examples, from week 0 to 52 in one trial, the serum creatinine increased by 0.086 (±0.005) mg/dL, the LDL cholesterol increased by 18 (±1) mg/dL, and the neutrophil count decreased by 1230 (±90) per mm3 [65].

The use, efficacy (particularly in patients resistant to initial DMARD therapy), and safety of baricitinib are described in more detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Baricitinib' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Baricitinib'.)

Upadacitinib — Upadacitinib is a selective JAK-1 inhibitor and is approved for RA patients who have failed TNF inhibitors due to lack of efficacy or tolerability [67]. Upadacitinib at the approved 15 mg and unapproved 30 mg dose was compared with standard-dose MTX in 840 RA patients naïve to MTX. The primary endpoint was the ACR50 response at week 12 and the proportion of patients achieving DAS28-CRP <2.6 at week 24. Both doses of upadacitinib were superior to MTX for the primary endpoints and superior to MTX in slowing radiographic progression. Adverse events were similar for the upadacitinib 15 mg dose and MTX but numerically more frequent with the 30 mg dose.

Filgotinib — Filgotinib is a selective JAK-1 inhibitor approved in multiple countries, but it was not approved in the United States. It is approved for RA patients who have failed one or more DMARDs at a dose of 100 to 200 mg daily as monotherapy or combination therapy. Filgotinib as 200 mg monotherapy or 100 or 200 mg as combination therapy was evaluated in MTX-naïve RA patients in a 52-week clinical trial with the primary endpoint of ACR20 response at week 24 [68]. Both combination therapies were statistically superior to MTX monotherapy in ACR response and secondary endpoints such as Health Assessment Questionnaire Disability Index (HAQ-DI). Filgotinib monotherapy ACR20 response (78 percent) was not statistically superior to MTX (71 percent), although it was superior in slowing radiographic progression at week 52. Adverse events were similar for both filgotinib and MTX.

The adverse effects and related concerns regarding the use of tofacitinib and the other JAK inhibitors, as well as the regulatory warnings and restrictions on drug use from the FDA and EMA, are described in detail separately. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Pretreatment screening and precautions' and "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Adverse effects'.)

Other agents

Azathioprine – Azathioprine (50 to 200 mg once daily) is another alternative to MTX, although its use has declined with the availability of other agents. Azathioprine may be a reasonable treatment option in several situations in which MTX is contraindicated, including liver or kidney disease, patients with RA-associated lung disease (eg, interstitial lung disease with functional decline or pneumonitis), pregnancy, or the absence of effective contraception, particularly in patients unable to use other agents. Neutropenia is the most common complication of azathioprine treatment, mandating close laboratory surveillance with its use.

Azathioprine was approved in 1981 by the FDA for use in RA. Clinical trial findings suggest that azathioprine is superior to placebo [69-73], comparably effective to parenteral gold [74], and probably less effective than MTX [75].

The use and safety of azathioprine in RA are described in more detail separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

Minocycline – Minocycline (100 mg twice daily) represents a potential alternative but rarely used treatment of mildly active RA. Minocycline exhibits modest benefit compared with placebo in trials involving patients with longstanding active RA, but greater benefit in rheumatoid factor (RF)-positive patients with RA for less than a year [76-79]. It was superior to HCQ in another study of RF-positive patients with early disease [80]. However, minocycline has not been directly compared with SSZ, MTX, or other major DMARDs in common use since the 1990s, and there are no data demonstrating that minocycline prevents the development of bone erosions or otherwise reduces joint injury. Adverse effects with minocycline include gastrointestinal upset, dizziness, and skin hyperpigmentation. A potential alternative to minocycline is doxycycline, although there are less data supporting use of doxycycline [81]. Minocycline, but not doxycycline, can occasionally lead to drug-induced lupus or vasculitis.

Others – Several other agents that are commercially available for the treatment of RA, including rituximab and sarilumab, as well as peficitinib, have not been evaluated in randomized trials for DMARD-naïve patients with early RA or compared with MTX in such patients; we thus prefer alternative medications. (See 'Anti-IL-6 receptor' above and 'JAK inhibitors' above.)

We reserve the use of rituximab as the initial agent for patients with a history of lymphoproliferative disease in whom other agents are contraindicated because of safety concerns and cost. In patients treated with rituximab who are unable to take MTX, we prefer to administer it in combination with LEF rather than as monotherapy. The use of rituximab and the evidence supporting its use in combination with LEF are described separately. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy", section on 'Methotrexate plus rituximab' and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Rituximab'.)

SPECIAL POPULATIONS — Some patients may be appropriate candidates for less toxic but potentially less efficacious therapies, while, in other patients, pregnancy concerns or preferences due to comorbidities that may be present can constrain or guide therapeutic choices. (See 'Limited arthritis' below and 'Pregnancy, comorbidities, and other special considerations' below.)

As an example, in rheumatoid arthritis (RA) patients with recurrent infections, biologics and Janus kinase (JAK) inhibitors would be relatively contraindicated; in such patients, disease-modifying antirheumatic drugs (DMARDs) such as hydroxychloroquine (HCQ), sulfasalazine (SSZ), and minocycline or doxycycline, which are not potent immunosuppressives, would be preferred therapies.

Limited arthritis

General approach — In patients with low disease activity, we suggest hydroxychloroquine (usually 200 to 400 mg daily, but no more than 5 mg/kg/day calculated based upon actual body weight) as the initial alternative DMARD to methotrexate (MTX), rather than SSZ or leflunomide (LEF). The dosing, adverse effects, and monitoring of HCQ are described in detail separately. (See "Antimalarial drugs in the treatment of rheumatic disease" and 'Hydroxychloroquine' below and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Prognosis'.)

In addition to starting a DMARD, we use nonsteroidal antiinflammatory drugs (NSAIDs) or glucocorticoids in many patients on a temporary basis to quickly achieve control of the signs and symptoms of disease. We then taper and withdraw the antiinflammatory medications once the DMARDs have taken effect. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Hydroxychloroquine' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Sulfasalazine' and "Initial treatment of rheumatoid arthritis in adults", section on 'Symptomatic treatment with antiinflammatory drugs'.)

We also use HCQ in patients with findings limited to mild inflammatory arthritis and a positive antinuclear antibody (ANA) test, in whom a distinction cannot be made between early RA, undifferentiated immune-inflammatory disease, and early systemic lupus erythematosus (SLE).

We prefer HCQ in these patient populations because this agent is very well tolerated, is effective, and has a very low risk of significant toxicity, although HCQ may be less effective than MTX, SSZ, and other DMARDs. (See 'Hydroxychloroquine' below.)

SSZ (begun at 500 mg twice daily and gradually increased [eg, by 500 mg per week] to up to 1000 to 1500 mg twice daily) may be used as an alternative to HCQ in this group of patients if needed (see 'Sulfasalazine' above). In patients whose clinical features suggest a possible evolving form of SLE, SSZ is a less attractive option, as sulfonamides have been implicated in occasional exacerbations of SLE.

Neither HCQ nor SSZ impair female fertility, and both are relatively safe if continuing use is essential in pregnancy; thus, they are especially suitable for patients who are planning to get pregnant, although SSZ has been associated with a reversible oligospermia in male patients. (See 'Pregnancy, comorbidities, and other special considerations' below and "Rheumatoid arthritis and pregnancy" and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases", section on 'Sulfasalazine'.)

Our approach is generally consistent with other major recommendations or guidelines [25,82]. The preferential use of HCQ and/or SSZ over MTX/LEF in patients with mildly active RA was conditionally recommended in the 2021 American College of Rheumatology (ACR) recommendations on the use of DMARDs in RA [2]. The recommendations of the European Alliance of Associations for Rheumatology (EULAR) also note that patients with low disease activity may not require MTX, which they otherwise suggest as the initial DMARD [83]. The EULAR recommendations favor limiting the use of HCQ monotherapy to patients with very mild disease and contraindications to other DMARDs.

Some rheumatologists favor the use of other medications, such as LEF or a biologic agent, in this patient subset because of their proven efficacy, long-term durability, and effectiveness as cotherapy with other agents. (See 'Nonbiologic traditional DMARD alternatives to methotrexate' above and 'Leflunomide' above and "General principles and overview of management of rheumatoid arthritis in adults", section on 'Prognosis'.)

If patients have greater disease activity, or if an adequate trial (12 to 16 weeks) of these medications proves inadequate, we then initiate therapy with another nonbiologic or a biologic DMARD or with a combination of DMARDs. (See "Initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

Hydroxychloroquine — HCQ is generally extremely well tolerated. The dosing, 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 'Routine eye examinations' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Administration, dosing, and monitoring'.)

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 [84,85]. Other antimalarial drugs may also be of benefit.

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 [86-89]. 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) [90]. 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) [86].

Radiographic deterioration was comparable at 12 months in patients randomized to either HCQ or placebo in the one study that examined this question [86].

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 rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate'.)

Pregnancy, comorbidities, and other special considerations — Pregnancy or anticipated pregnancy, absence of adequate contraception, breastfeeding, and the presence of comorbidities, such as renal or hepatic disease, may affect medication choices and may influence the degree of risk inherent in attempting to reach a goal of remission or of low disease activity in a given patient.

As examples, MTX and LEF are contraindicated in women planning pregnancy and who are pregnant, while HCQ and SSZ are generally acceptable. Similarly, patients with liver disease who need to avoid MTX should also avoid LEF but may tolerate SSZ. The use of any DMARD depends upon various contextual issues. A number of medical conditions that often coexist with or result from RA may also influence the choice of medications. The approach to treatment in the presence of these conditions is discussed in more detail separately. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Tight control' and "Rheumatoid arthritis and pregnancy" and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases".)

MONITORING AND REEVALUATION — During the initial treatment of patients with 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 [48,91,92]. We advise the regular reevaluation of disease activity using a quantitative composite measure at each assessment (eg, Disease Activity Score in 28 joints [DAS28], Clinical Disease Activity Index [CDAI], or Routine Assessment of Patient Index Data [RAPID]-3) [3,4]. 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 disease activity and physical function".)

RESISTANT TO INITIAL DMARD THERAPY — In patients treated with hydroxychloroquine (HCQ) or sulfasalazine (SSZ) who fail to achieve remission or 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, a tumor necrosis factor [TNF] inhibitor or leflunomide [LEF]) or combination therapy. (See "Initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

In patients with active disease, who have received monotherapy with LEF or a biologic agent but fail to achieve remission or low disease activity within three months of initiating therapy, or who require more than 5 to 7.5 mg/day of prednisone or equivalent to maintain low disease activity, we initiate combination therapy, using combinations of nonbiologic DMARDs (eg, LEF plus SSZ) or of nonbiologic DMARDs with a single biologic agent (eg, LEF plus a TNF inhibitor), as we would with patients who fail to respond to methotrexate (MTX) or biologic monotherapy. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

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 education: Disease-modifying antirheumatic drugs (DMARDs) (The Basics)")

Beyond the Basics topics (see "Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient education: Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

The same general management principles and precautions used in patients with rheumatoid arthritis (RA) who are treated with methotrexate (MTX) apply to patients being treated for RA with an alternative to MTX. (See 'General principles' above.)

The choice of the disease-modifying antirheumatic drug (DMARD) to employ as an alternative to MTX is largely based upon evidence from indirect comparisons and limited head-to-head comparisons; disease severity, comorbidities, patient preferences regarding relative risks and benefits and route of administration; and regulatory, insurance, and cost limitations. (See 'Approach to management' above and 'Choice of therapy' above.)

In most patients with active RA who are unable to use MTX as their initial DMARD, we suggest leflunomide (LEF) rather than another conventional synthetic DMARD (csDMARD) or a biologic DMARD (Grade 2C). We generally prefer LEF (20 mg daily) over sulfasalazine (SSZ) because it may have greater efficacy, especially for the treatment of moderate to severely active RA. The advantages of LEF over tumor necrosis factor (TNF) inhibitors are that it is taken orally and has a lower risk of serious adverse effects, including infection. However, other agents are reasonable alternatives to LEF, particularly in the following settings:

Patients with liver disease – In patients unable to use MTX because of liver disease, LEF should also be avoided and an alternative such as SSZ (1 to 1.5 g twice daily) or a TNF inhibitor (eg, etanercept 50 mg subcutaneously once weekly or adalimumab 40 mg subcutaneously every two weeks), unless otherwise contraindicated, should be used. (See 'Sulfasalazine' above and 'Tumor necrosis factor inhibitors' above.)

Patients with high disease activity and significant functional impairment – TNF inhibitors (eg, etanercept or adalimumab) are reasonable alternatives for initial therapy in patients with moderate to high disease activity or significant functional impairment who are not restricted by regulatory or cost constraints. (See 'Tumor necrosis factor inhibitors' above.)

Patients with mild disease – In patients who have low disease activity, we suggest hydroxychloroquine (HCQ) as the initial alternative DMARD to MTX, rather than a more potent csDMARD or biologic DMARD (Grade 2C). We would also use HCQ in patients with findings limited to mild inflammatory arthritis and a positive antinuclear antibody (ANA) test, in whom a distinction cannot be made between early RA and early systemic lupus erythematosus (SLE). The typical dose is 200 to 400 mg daily, but no more than 5 mg/kg/day calculated based upon actual body weight. LEF and SSZ are other reasonable alternatives for this population. (See 'Limited arthritis' above and 'General approach' above and 'Hydroxychloroquine' above.)

Women planning pregnancy – Reasonable options for women planning pregnancy include SSZ, HCQ in patients with mild disease, or a TNF inhibitor, while LEF should be avoided. The choice of drugs in pregnancy, including choices between TNF inhibitors, is described separately. (See 'Pregnancy, comorbidities, and other special considerations' above and "Rheumatoid arthritis and pregnancy".)

Additional reasonable alternatives that can be effective as initial monotherapy are abatacept and tocilizumab, biologic DMARDs usually administered by subcutaneous injection. However, abatacept and tocilizumab are rarely available for this group of patients due to regulatory and/or cost constraints. Patient preference regarding route of administration, regulatory and cost constraints, and clinician experience with these agents are the major factors usually determining choice in a given patient. (See 'Choice of therapy' above and 'Other alternative agents' above.)

During the initial treatment of patients with 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 or low disease activity within three months of initiating therapy or who require more than 5 to 7.5 mg/day of prednisone or equivalent glucocorticoid to maintain a state of remission or low disease activity, we use a more potent DMARD or combination of DMARDs rather than continuing the same treatment for a greater duration. Treatment of such patients is discussed in detail separately. (See 'Monitoring and reevaluation' above and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Peter H Schur, MD, and Sir Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS, who contributed to an earlier version of this topic review.

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Topic 7477 Version 37.0

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