Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy

Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy

Authors
Stanley Cohen, MD
Amy Cannella, MD, MS, RhMSUS

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: Apr 01, 2016.

INTRODUCTION — The treatment of rheumatoid arthritis (RA) is directed toward the control of synovitis and the prevention of joint injury. In patients with disease resistant to methotrexate (MTX) monotherapy, and whose condition is also resistant to treatment with an initial course of biologic disease-modifying antirheumatic drug (DMARD), usually a tumor necrosis (TNF) inhibitor, typically administered in combination with MTX, timely adjustments in the treatment regimen are required to achieve effective disease control and to prevent damage to the joints. The achievement and maintenance of tight control of disease by use of DMARDs is associated with improved outcomes, as these medications and strategies have the potential to control synovitis and to slow or even stop radiographic progression [1-11]. (See "General principles of management of rheumatoid arthritis in adults", section on 'Tight control'.)
The treatment of active RA in adults who are resistant to initial therapy with a biologic DMARD, usually a TNF inhibitor in the context of ongoing treatment with MTX, will be reviewed here. The general principles of the management of RA, the initial treatment of RA, the treatment of patients resistant to initial therapy with nonbiologic DMARDs (eg, MTX monotherapy), and the approach to RA patients with severe structural damage are presented separately. (See "General principles of management of rheumatoid arthritis in adults" and "Initial treatment of mildly active rheumatoid arthritis in adults" and "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'Monitoring and reevaluation' and "Total joint replacement for severe rheumatoid arthritis" and "Evaluation and medical management of end-stage rheumatoid arthritis" and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy".)
GENERAL PRINCIPLES AND APPROACH
Principles of management — There are several general principles that are important in the management of all patients with rheumatoid arthritis (RA). Briefly, these include:
●Achievement and maintenance of tight control of disease activity, defined as remission or a state of low disease activity, without compromising safety
●Treatment of all patients diagnosed with RA with disease-modifying antirheumatic drug (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 an expert in the treatment of RA, typically a rheumatologist
These principles are discussed in detail elsewhere. (See "General principles of management of rheumatoid arthritis in adults".)
It is important to determine whether joint symptoms in patients with persistently symptomatic RA are due to active inflammatory arthritis or are the result of structural damage that is unlikely to respond to antiinflammatory drugs and to nonbiologic or biologic DMARDs. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice" and "General principles of management of rheumatoid arthritis in adults", section on 'Assessment of disease activity'.)
Definition of resistance to DMARDs — Resistance or an inadequate response to initial or subsequent DMARD therapy is defined as one of the following:
●Failure to achieve remission or low disease activity within three to six months of initiating the nonbiologic (traditional) or biologic DMARD or antirheumatic kinase inhibitor in maximally tolerated doses within the usual therapeutic range.

A therapeutic trial of greater than three months is generally used in patients with partial responses showing progressive improvement, particularly in those with low to moderate levels of disease activity and with limited functional impairment. Treatment should be appropriate for the patient’s overall medical status and comorbidities, and should take into consideration the patient’s treatment goals and preferences. (See "Assessment of rheumatoid arthritis activity in clinical trials and clinical practice", section on 'Remission' and "Initial treatment of moderately to severely active rheumatoid arthritis in adults" and "General principles of management of rheumatoid arthritis in adults", section on 'Tight control' and "General principles of management of rheumatoid arthritis in adults", section on 'Other considerations in RA management'.)
●A requirement, in addition to DMARDs, for chronic glucocorticoid therapy in a dose of greater than about 5 to 7.5 mg/day of prednisone or equivalent to achieve or maintain remission or low disease activity after three to six months of treatment with DMARDs.
●A requirement for multiple courses of treatment with glucocorticoids, in excess of doses used for chronic therapy, for the treatment of recurrent disease flares in patients whose DMARD doses have been increased to the maximally tolerated or acceptable level within the usual therapeutic range.
●Continued progression of erosive disease or structural damage that is not accounted for by prior mechanical destabilization of the joints.
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 therapies and DMARDs. These interventions, including patient education, vaccinations, and others, are discussed in detail elsewhere. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis".)
PRETREATMENT INTERVENTIONS — A number of important precautions should be taken before using disease-modifying antirheumatic drugs (DMARDs), including laboratory assessment (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 (TB) infection. Precautions relevant to the use of each new agent being prescribed should be reviewed before initiating such therapy to confirm that all appropriate measures have been performed. A chest radiograph should be obtained prior to initiating treatment with methotrexate (MTX). These issues are discussed in detail elsewhere. (See "Nonpharmacologic therapies and preventive measures for patients with rheumatoid arthritis", section on 'Vaccinations' and "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Diagnosis of latent tuberculosis infection (tuberculosis screening) in HIV-uninfected adults" and "Major side effects of low-dose methotrexate", section on 'Pulmonary toxicity' and "General principles of management of rheumatoid arthritis in adults", section on 'Pretreatment evaluation'.)
PHARMACOTHERAPY
Approach to pharmacotherapy — The choice of the disease-modifying antirheumatic drug (DMARD) regimen in patients resistant to initial biologic DMARD treatment depends largely upon the responses to the specific medications that have been used previously:
●In patients who do not respond adequately to therapy with methotrexate (MTX) plus an initial tumor necrosis factor (TNF) inhibitor within three to six months, we generally switch to a different TNF inhibitor and continue therapy with MTX (see 'Resistant to one TNF inhibitor' below). An alternative approach in this setting, particularly in patients with primary lack of responsiveness rather than drug intolerance or secondary failure due to loss of efficacy, is switching to another biologic agent with a different mechanism of action, rather than a second TNF inhibitor. In patients who have not been treated previously with “triple therapy” (the nonbiologic DMARD regimen of MTX, hydroxychloroquine [HCQ], and sulfasalazine [SSZ]), this combination is another alternative that may be used, potentially concurrently with a TNF inhibitor in patients for whom the TNF inhibitor was judged to be partially effective.
●In patients who do not respond adequately to the therapies above, including MTX and trials of one or two TNF inhibitors, we use abatacept, tocilizumab, rituximab, or tofacitinib, an antirheumatic kinase inhibitor, in place of the TNF inhibitor (see 'Resistant to two TNF inhibitors' below). We generally continue MTX in such patients, unless contraindicated, to improve the degree of clinical and radiographic benefit and to inhibit the development of antibodies directed at the biologic agent that can reduce efficacy.
●In patients with an inadequate response to the standard therapeutic approaches, additional alternatives include other combinations of potentially efficacious nonbiologic DMARDs for which some supportive data exist, but which have not yet been employed, or anakinra, another biologic agent. (See 'Resistant to standard therapies' below.)
Drug choice should be tailored to the individual patient based upon their comorbid conditions, fertility considerations, and preference for route of administration (oral versus parenteral), as well as regulatory or insurance limitations and cost to the patient.
Importantly, we do NOT recommend combinations of any of the biologic DMARDs or a biologic DMARD with tofacitinib. These regimens are associated with an increased frequency of severe adverse effects, particularly serious infections, compared with combinations of a nonbiologic and biologic DMARD. (See "General principles of management of rheumatoid arthritis in adults".)
Resistant to one TNF inhibitor — In patients who do not respond adequately to therapy with an initial TNF inhibitor within three to six months, we suggest switching to a different TNF inhibitor and continuing therapy with MTX. The available agents are similarly effective, and the specific agents, dosing, safety, and additional discussion of efficacy are presented separately (see "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'MTX plus TNF inhibitor'). An inadequate response to one anti-TNF agent does not predict resistance to other agents in this class, although inefficacy and discontinuation rates increase with successive switches. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Definition of resistance to initial therapy with nonbiologic DMARDs'.)
In patients in whom triple therapy was not employed prior to the initiation of MTX plus anti-TNF therapy an effective alternative to switching to another biologic is a switch to (or addition of) triple therapy, which has been shown to result in significant improvement in this setting [12]. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Efficacy of triple therapy versus MTX/TNF inhibitor'.)
Some experts advocate switching to another class of biologic in patients who have experienced a serious adverse event (as defined by the US Food and Drug Administration [FDA]) with an initial TNF inhibitor [13] or in those who have had little or no initial response (primary failures). The FDA definition of a serious adverse event includes an adverse event associated with the use of a medical product that resulted in a life-threatening event, hospitalization, prolongation of a hospitalization, disability or permanent damage, a congenital anomaly or birth defect in a child of a parent using the medication, or an adverse event requiring intervention to prevent permanent impairment or damage.
Limited randomized trials, several large registry-based studies, and case series have demonstrated the benefit of switching from one biologic DMARD to another, if inefficacy or toxicity limits the use of a given agent [14-24]. This is true both with switches from one to another TNF inhibitor and switches between classes of biologic agent.
The best data illustrating that switching to a second TNF inhibitor is effective after discontinuation of a first are from a randomized trial of golimumab as the second agent, although there is less clinical experience with golimumab than with several of the other TNF inhibitors [15]. In this trial, 461 patients with active rheumatoid arthritis (RA) despite prior use of at least one TNF inhibitor were randomly assigned to golimumab or placebo while continuing stable doses of baseline nonbiologic DMARDs (MTX, SSZ, and/or HCQ), glucocorticoids, and nonsteroidal antiinflammatory drugs (NSAIDs). The prior TNF inhibitor could have been discontinued due to either ineffectiveness (58 percent) or other factors unrelated to effectiveness, including intolerance or inaccessibility (53 percent); some discontinued the first TNF inhibitor for multiple reasons. Among those who had discontinued the first TNF inhibitor due to lack of effectiveness, patients in the combined golimumab group (who received either 50 or 100 mg every four weeks) were significantly more likely to achieve an ACR (American College of Rheumatology)20 or higher response at week 14 (39 versus 18 percent). Patients who discontinued the first drug for reasons other than ineffectiveness were also more likely to achieve at least an ACR20 response with golimumab (34 versus 20 percent). There was no increase in serious adverse events in patients on golimumab compared with those on placebo. The results of this trial are consistent with findings from observational studies of other TNF inhibitors.
The relative benefits of switching to a second or a third TNF inhibitor (etanercept [ETN], infliximab, or adalimumab) were examined in a prospective observational study of 373 patients in the South Swedish Arthritis Treatment Group register [18]. After three months of treatment, patients receiving their first compared with their second anti-TNF agent and patients receiving their second compared with their third anti-TNF agent were more likely to achieve an ACR20 (61 versus 51 versus 35 percent, respectively) or ACR50 response (37 versus 27 versus 18 percent, respectively). European League Against Rheumatism (EULAR) overall response rates in the three groups were 76 versus 71 versus 58 percent.
No randomized trials have been performed to directly compare different biologic agents in patients who have had an inadequate response to a TNF inhibitor, and results of indirect comparisons and observational studies are inconsistent. Indirect comparisons based upon data from the small number of available trials have not shown significant differences in benefit between golimumab and biologic DMARDs from other classes (with which there are less experience in this setting), including rituximab, tocilizumab, and abatacept [25,26]. However, observational studies suggest that patients with an inadequate response to one TNF inhibitor may benefit from a switch to rituximab instead of another TNF inhibitor [27-29]. Greater relative benefit of rituximab was seen in patients with seropositive compared with seronegative RA [27].
Resistant to two TNF inhibitors — In patients who do not respond adequately to three- to six-month trials of each of two TNF inhibitors, or who are unable to take a TNF inhibitor, we suggest the use of abatacept, tocilizumab, or rituximab, biologic agents which may all be effective in patients who have not responded adequately to MTX plus a TNF inhibitor, while continuing MTX (unless use is contraindicated by prior intolerance, pregnancy, pulmonary or renal disease, or other comorbidities). Tofacitinib, the orally-administered kinase inhibitor available for use in the United States, is also an alternative in this setting, although there is less experience with this agent, and its role will be better defined over time with wider use and further study. No single agent is generally preferred in this setting, and several factors should be considered in choosing which drug to use. (See 'Choice of therapy' below.)
Because the likelihood of a response decreases with second switches of TNF inhibitors, a change to a biologic DMARD other than a TNF inhibitor is suggested after the failure of two such agents. There are no randomized trials that have evaluated this hypothesis. (See 'Resistant to one TNF inhibitor' above.)
In patients who discontinue the second TNF inhibitor, analyses of data from a large national patient registry in Great Britain suggested that discontinuation was primarily due to the same reason for which the first drug was stopped (inefficacy or toxicity) [17].
Choice of therapy — The choice between abatacept, tocilizumab, rituximab, and tofacitinib depends upon several factors, which vary in importance in different patients. These factors include patient preference; regulatory, insurance, and cost limitations; comorbidities; and clinician experience. They have not been directly compared, but abatacept, tocilizumab, and rituximab appear comparable in indirect comparisons of randomized trial data in a meta-analysis [26]. We generally take the following approach:
●We usually use abatacept, rituximab, or tocilizumab as the first choice in this group of patients in the seropositive subset. In seronegative patients, we prefer abatacept or tocilizumab. In patients who experience adverse effects from these agents, the immunosuppressive or immunomodulatory actions of abatacept or tocilizumab are more rapidly reversed than those of rituximab, whose effects may last for several months or longer. Additionally, rituximab use may be very rarely associated with devastating illness due to reactivation of the polyomavirus JC (JC virus), progressive multifocal leukoencephalopathy (PML). (See "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Rituximab' and "Progressive multifocal leukoencephalopathy: Epidemiology, clinical manifestations, and diagnosis".)
●In older patients with more comorbidities, we prefer abatacept over tocilizumab or rituximab. There is more limited experience with tocilizumab than with abatacept or rituximab, and some concerns remain regarding potential toxicity. Indirect comparisons suggest that abatacept may have fewer adverse effects than the other biologic agents used in RA [30]. In addition, in a cohort study using Medicare data and involving 31,801 new treatment episodes for RA with a biologic agent, patients with prior exposure to a biologic had a significantly higher risk for hospitalized infections upon exposure to etanercept, infliximab, or rituximab, compared with abatacept (HR 1.24, 95% CI 1.07-1.45; HR 1.39, 95% CI 1.21-1.53; and HR 1.36, 95% CI 1.21-1.53, respectively) [31]. Numerical trends suggesting increased rates with the other agents were not statistically significant. Crude incidence rates ranged from 13.1 (abatacept) to 18.7 (rituximab) per 100 patient-years.
In patients with chronic obstructive pulmonary disease (COPD), if abatacept is used it should be with particular caution because of the higher rates of COPD exacerbations and respiratory tract infections reported in such patients in the randomized trials of this agent.
●Rituximab may be preferred in patients in whom monthly drug administration may be problematic, as a treatment course of two intravenous infusions is administered no more frequently than every six months. Patients with rheumatoid factor or with anti-citrullinated peptide antibodies may have a greater response to the drug than seronegative patients [32,33]. Otherwise, the efficacy and safety of rituximab in patients with RA appear similar to those of other biologic agents [30,34].
●The relative role of tofacitinib in patients who have had an inadequate response to other DMARDs is unclear. A potential advantage of this medication is that it is administered orally. Data from patients with RA enrolled in the tofacitinib randomized trials suggest that tofacitinib is associated with similar rates of infection and overall mortality to those reported in RA for other biologic agents [35].
●We prefer these agents (abatacept, tocilizumab, rituximab, and tofacitinib) over anakinra, as they all appear more effective than anakinra, based upon their comparability to biologic DMARDs that have been shown superior to anakinra in indirect comparisons [36]. (See 'Resistant to standard therapies' below.)
Drug dosing, efficacy, and safety
Abatacept — The dosing and administration of abatacept in patients with rheumatoid arthritis (RA) are described separately (see "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'MTX plus abatacept'). We use abatacept in combination with MTX unless use of MTX is contraindicated.
The use of abatacept in patients with RA in general, evidence supporting such use, and the adverse effects of abatacept are also reviewed in detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Efficacy of MTX/TNF inhibitor versus MTX/abatacept' and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'MTX plus abatacept' and "T-cell targeted therapies for rheumatoid arthritis", section on 'Abatacept'.)
A randomized trial and a larger open-label study have described the benefits of abatacept compared with placebo in patients who have had an inadequate response to a TNF inhibitor [20,37]. In the randomized trial involving 391 patients, patients receiving abatacept were significantly more likely compared with placebo-treated patients to achieve at least 20 percent improvement in the level of disease activity after 24 weeks of therapy (ACR20 of 50 versus 20 percent) [20]. The rate of serious infections was the same in both groups (2.3 percent).
Tocilizumab — Tocilizumab, a humanized anti-human interleukin (IL)-6 receptor antibody, can be administered either by intravenous infusion or by subcutaneous injection. When administered intravenously, it is given every four weeks (at an initial dose of 4 mg/kg per infusion, which may be increased to 8 mg/kg per infusion, based upon the clinical response, to a maximum of 800 mg/infusion). When taken subcutaneously in patients <100 kg, the dose is 162 mg every other week, which may be increased to every week based upon the clinical response; in patients ≥100 kg, the dose is 162 mg every week. The subcutaneous route of administration (162 mg) has comparable efficacy and safety when compared with the intravenous route (8 mg/kg) [38]. We use tocilizumab in combination with MTX, unless MTX is contraindicated.
The efficacy and safety of tocilizumab in RA have been characterized in meta-analyses of randomized trials of the drug as monotherapy or together with MTX compared with placebo. This evidence is reviewed in detail separately. (See "Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL", section on 'Tocilizumab'.)
Tocilizumab is available for use in RA patients with active disease despite treatment with MTX, but we use it primarily in patients with RA who have not responded adequately to TNF inhibitors. In a randomized trial involving 499 patients with an inadequate response to TNF inhibitor therapy, the use of tocilizumab (8 or 4 mg/kg administered intravenously every four weeks), together with continued treatment with MTX, significantly improved treatment outcomes at six months compared with placebo plus MTX (ACR20 of 50 and 30 percent versus 10 percent) [22]. Substantial improvement was noted within four weeks and may be maintained for at least several years in long-term follow-up [24]. The rates of serious adverse events, serious infections, and adverse events leading to drug discontinuation were similar in all three groups; adverse events that were numerically more common in patients on tocilizumab included infections (49 and 47 percent versus 41 percent), gastrointestinal symptoms (37 and 33 percent versus 19 percent), and rash (22 and 31 percent versus 14 percent).
Tocilizumab was compared directly with adalimumab as monotherapy for patients with active RA who were intolerant to MTX or who were considered inappropriate candidates for continued treatment with MTX [39]. In this randomized 24-week trial involving 326 patients, tocilizumab (8 mg/kg administered intravenously every four weeks plus subcutaneous placebo every two weeks) was compared with adalimumab (40 mg administered subcutaneously every two weeks plus intravenous placebo every four weeks). Tocilizumab use resulted in a significantly greater reduction in the disease activity score using 28 joints and the erythrocyte sedimentation rate (DAS28-ESR decrease of -3.3 versus -1.8, difference of -1.5, 95% CI -1.8 to -1.1). A proportionately smaller but statistically significant difference in the degree of improvement was noted using the Clinical Disease Activity Index (CDAI decrease of -23.8 versus -18.9, difference of -4.9, 95% CI -8.3 to -1.5), which is independent of the reduced levels of acute phase reactants that may occur disproportionately with tocilizumab, unlike the DAS28-ESR. A trend toward greater improvement in the Health Assessment Questionnaire (HAQ) score did not achieve statistical significance. Only the higher dose of tocilizumab was used in this trial; there was no comparison with the more standard 4 mg/kg dose. Serious adverse effects did not differ between the groups, but laboratory abnormalities were more common with tocilizumab.
A dose adjustment or drug discontinuation may be required in patients with significant liver enzyme (aminotransferase) elevations, neutropenia, or thrombocytopenia. Other adverse effects include serious infections, including mycobacterial and other opportunistic infections. The risk of adverse effects is greater in patients on concomitant immunosuppressive therapy. Hyperlipidemia may occur and should be managed according to available guidelines. Intestinal perforations have been reported, especially in older patients and in those with a history of diverticulitis, which is a contraindication to the use of tocilizumab. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention" and "Treatment of lipids (including hypercholesterolemia) in secondary prevention".)
An analysis of data from multiple European patient registries, involving 2057 patients treated with tocilizumab, found that cotherapy of tocilizumab with a nonbiologic (traditional) DMARD or DMARD combination had similar efficacy to tocilizumab monotherapy, although patients receiving tocilizumab alone discontinued the therapy earlier [40]. Over 80 percent of the study patients on a nonbiologic DMARD were receiving MTX.
Rituximab — Rituximab is a monoclonal anti-CD20 antibody that depletes B cells. It is administered intravenously (1000mg/dose) on days 1 and 15 of therapy, usually 30 minutes following intravenous administration of methylprednisolone (100 mg), which can reduce the incidence and severity of infusion reactions. Subsequent courses are usually given every 6 to 12 months if clinically indicated, based upon disease activity. Similarly, we generally wait six months after administration of rituximab before switching to an alternative medication for lack of efficacy or for adverse effects because of the duration of its biologic effects. Rituximab is given in combination with ongoing MTX treatment unless MTX is contraindicated. The use of rituximab in the treatment of RA, additional evidence supporting such use, and the adverse effects of rituximab are reviewed in detail separately. (See "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Rituximab'.)
The efficacy of rituximab plus continued therapy with MTX in patients with an inadequate response to a TNF inhibitor was shown in comparison with placebo plus continued MTX in a randomized trial involving 520 patients [21]. At six months, significantly more patients receiving rituximab showed at least 20 percent improvement in clinical activity compared with placebo-treated patients (ACR20 of 51 versus 18 percent). Additional evidence suggests benefit with retreatment six months after an initial course [41]. Additionally, a registry-based study suggested that, when the reason for stopping a TNF inhibitor was lack of effect rather than an adverse event, rituximab resulted in a greater decrease in disease activity compared with treatment with another TNF inhibitor (DAS28 decrease of -1.34 versus -0.93) [19].
Tofacitinib — Tofacitinib is an orally administered Janus kinase (JAK) inhibitor that decreases signalling by a number of cytokine and growth factor receptors. It is taken in a dose of 5 mg twice daily. Tofacitinib is effective and can be used as monotherapy or combined with MTX (our usual approach) or other nonbiologic DMARDs in patients with moderately to severely active RA who have had an inadequate response to MTX [42-48]. Other nonbiologic DMARDs may be used as an alternative to MTX in patients intolerant of MTX therapy. It should NOT be taken in combination with biologic agents or with other potent immunosuppressants, such as azathioprine or cyclosporine. The evidence supporting the use of tofacitinib in patients with RA is reviewed here briefly and is discussed in more detail separately. (See "Cytokine networks in rheumatic diseases: Implications for therapy", section on 'JAK inhibition'.)
The efficacy and safety of tofacitinib in RA have been evaluated in a series of randomized trials in patients with an inadequate response to MTX or another traditional or biologic DMARD [42-47]. It has also been compared as monotherapy with MTX in patients naïve to these agents [48]. As examples:
●Tofacitinib can be effective as monotherapy in patients with an inadequate response to MTX. In a randomized trial involving 611 patients with an inadequate response to at least one nonbiologic or biologic DMARD (usually MTX), tofacitinib monotherapy (5 mg twice daily) resulted significantly more often in reductions in signs and symptoms of active RA after three months of treatment, compared with placebo (ACR20 of 60 versus 27 percent) [42].
●Tofacitinib has also shown benefit as cotherapy with MTX in patients who have not had an adequate response to MTX alone [43,44,46]; it was also comparably effective to a TNF inhibitor in this setting:
•A trial involving 797 patients with active RA and inadequate responses to MTX showed significantly greater benefit at six months for continued MTX plus 5 or 10 mg twice daily of tofacitinib compared with MTX plus placebo (ACR20 of 52 and 62 percent versus 25 percent) [44]. At six months, those treated with tofacitinib demonstrated improved HAQ Disability indices (HAQ-DI –0.4 and -0.54 versus -0.15) and smaller increases in the degree of radiographic injury, although the reduction in radiographic change in those receiving the manufacturer’s recommended dose for clinical use (5 mg twice daily) did not reach statistical significance.
•In a randomized trial involving 717 patients, tofacitinib (5 mg twice daily) and adalimumab (40 mg administered subcutaneously every two weeks) showed similarly significant benefit compared with placebo after six months in patients with active RA who had had an inadequate response to MTX and who continued MTX cotherapy (ACR20 of 52 and 47 percent versus 28 percent, respectively) [43].
●Tofacitinib has also been shown to have efficacy in patients who have not responded adequately to TNF inhibitor therapy. In a randomized trial involving 399 patients with an inadequate response to MTX plus a TNF inhibitor, the addition of tofacitinib (5 or 10 mg twice daily) to MTX, compared with placebo plus MTX, resulted at three months in a significantly greater response rate (ACR20 of 42 and 48 percent versus 24 percent) and in significantly greater reductions in the degree of disability (HAQ-DI -0.43 and -0.46 versus -0.18) [45].
The relative safety of tofacitinib has generally appeared similar to that of biologic DMARDs, including increased risk of infections and liver function test abnormalities; additional concerns that require attention in clinical use include neutropenia, lymphopenia, hyperlipidemia, and, possibly, increased serum creatinine [42,43,49-51]. Gastrointestinal perforations have also been reported. An increased risk of herpes zoster was reported compared with placebo and the adalimumab-treated patients.
The relative safety of tofacitinib was evaluated in an analysis of the data from patients in the randomized trials and long-term extension studies of tofacitinib, including 4789 patients with 8460 patient-years of exposure to the drug [35]. The frequency of serious infections with tofacitinib was 3.09 events/100 patient-years (95% CI 2.73-3.49) and was stable over time; the frequency of all-cause mortality was 0.30 events/100 patient-years (95% CI 0.20-0.44). These rates were comparable to those previously reported in patients with RA receiving biologic DMARDs. Factors independently associated with an increased risk of serious infection with tofacitinib use were age, glucocorticoid dose, diabetes, tofacitinib dose, and lymphocyte counts of less than 0.5 x 10³/mm³. Patients should discontinue tofacitinib if lymphocyte counts drop below this level.
Herpes zoster was reported in 5 percent of patients (239 cases) in the trials and extension studies; the risk of herpes zoster was significantly increased in patients receiving tofacitinib compared with those receiving placebo (incidence ratio 4.4 per 100 patient-years, 95% CI 3.8-4.9) [52]. Only one case was multidermatomal, and none involved visceral dissemination or death. The only factors independently associated with increased risk of herpes zoster with tofacitinib use were older age and participation in the trials in Asia. If possible, vaccination with Zostavax is suggested prior to initiation of tofacitinib.
The need for concurrent MTX therapy with use of tofacitinib is uncertain, and has not been evaluated in randomized trials. Studies are ongoing to determine if combination therapy is superior to monotherapy.
Resistant to standard therapies — There are several options in patients who are unable to take or who have an inadequate response to TNF inhibitors, abatacept, tocilizumab, rituximab, and tofacitinib. The choice between these further options depends upon patient preferences regarding route of administration, patient comorbidities, and clinician preference based upon degree of experience with a given agent. There have been no head-to-head comparisons of these therapies.
●Nonbiologic (traditional) DMARDs – Treatment options in this setting should include the use of nonbiologic DMARDs, such as leflunomide (LEF), or DMARD combinations, such as triple therapy or MTX plus LEF, if they were not used in the original sequence of drug regimens in a given patient. These agents may be tried before less effective biologic agents, such as anakinra, or before the other nonbiologic DMARDs used infrequently in practice, such as those mentioned below. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Leflunomide'.)
●Anakinra – The interleukin (IL)-1 receptor antagonist, anakinra, can be used in combination with MTX but appears less effective than other biologic DMARDs in RA [36]. Its effectiveness in patients who have failed to respond to MTX plus a TNF inhibitor has not been evaluated. (See "Randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit IL-1, IL-6, and RANKL", section on 'Anakinra'.)
●Other nonbiologic traditional DMARDs – Other nonbiologic DMARDs that have less efficacy, greater toxicity, or both, compared with other available medications are listed below. Azathioprine and minocycline may be utilized as monotherapy, but also in combination regimens.
•Azathioprine (see "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Use in rheumatic diseases')
•Gold (see "Use of gold compounds in rheumatic diseases", section on 'Efficacy of parenteral gold in RA')
•Cyclosporine (see "Randomized clinical trials of combinations of nonbiologic DMARDs in rheumatoid arthritis", section on 'Cyclosporine and MTX')
•Minocycline or doxycycline (see "Initial treatment of mildly active rheumatoid arthritis in adults", section on 'Other therapies')
REEVALUATION AND MONITORING — Disease activity and the response to therapy should be regularly reassessed, along with monitoring for drug toxicities, every four to eight weeks following a change in the treatment regimen until the patient is stable and until disease is under control [8,53-55]. Subsequently, assessments should not be less frequent than every three to six months. The approach to reevaluation and monitoring of these patients is described in more detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Reevaluation and monitoring'.)
SYMPTOMATIC DRUG THERAPY — Antiinflammatory drugs are used as a supplement to disease-modifying antirheumatic drugs (DMARDs) under several conditions, including as bridging therapies until newly-instituted DMARD regimens become effective, as adjuncts to DMARDs on a chronic basis, and for the management of disease exacerbations (flares) (see 'Antiinflammatory therapy' below and 'Drug therapy for flares' below). Analgesic effects of nonsteroidal antiinflammatory drugs (NSAIDs) or acetaminophen may also give additional relief. (See 'Analgesics' below.)
Antiinflammatory therapy — We use NSAIDs or systemic and/or intraarticular glucocorticoids when needed for ongoing control of inflammation while awaiting the response to modifications in DMARD therapy. Glucocorticoids can help to rapidly control inflammation and to improve symptoms. However, they should be used in the lowest dose required once such control is achieved, and they should be tapered and discontinued as soon as feasible. Some patients require ongoing therapy with low doses of glucocorticoids to maintain remission or a low level of disease activity. (See "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'NSAIDs' and "Initial treatment of moderately to severely active rheumatoid arthritis in adults", section on 'Glucocorticoids' and "Use of glucocorticoids in the treatment of rheumatoid arthritis".)
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 by 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. The treatment of such flares is described in detail elsewhere. (See "Clinical manifestations of rheumatoid arthritis" and "Use of glucocorticoids in the treatment of rheumatoid arthritis" and "General principles of management of rheumatoid arthritis in adults", section on 'Assessment of disease activity' and "General principles of management of rheumatoid arthritis in adults", section on 'Drug therapy for flares'.)
Analgesics — In addition to the medications noted above, including NSAIDs, which also have analgesic effects, we use other analgesic medications, such as acetaminophen and/or tramadol, for additional pain relief, if required. We generally avoid the use of potent opioids because pain can be controlled in most patients with RA by effective use of antiinflammatories and DMARDs that control the disease process. Patients without evidence of very significant joint injury 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, neuropathy, or others).
DURATION OF THERAPY — Most patients with rheumatoid arthritis (RA) require sustained therapy and adjustments in their treatment regimen over months to years to achieve treatment goals. In the minority of patients who achieve a sustained clinical remission of greater than one year, we cautiously try to reduce nonbiologic and biologic disease-modifying antirheumatic drug (DMARD) doses while maintaining close monitoring to facilitate recognition of any recurrence of disease activity. We generally avoid discontinuing all DMARD treatment.
Continued close monitoring is required in patients who discontinue or reduce any of their medications. The risk of disease recurrence in such patients is high, and flares of disease may occur even several years after stopping therapy [56-60]. Moreover, clinical remission can be difficult to achieve upon resumption of DMARD therapy. Our approach to tapering of DMARD therapy in patients in remission is discussed in more detail separately. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Duration of therapy'.)
SPECIAL POPULATIONS
Pregnancy — Considerations relevant to the management of rheumatoid arthritis (RA) during pregnancy are reviewed separately. (See "Rheumatoid arthritis and pregnancy" and "Use of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy and lactation".)
Resource-poor settings — Some patients may not have adequate access to healthcare resources. For patients with RA, this can result in limited or no access to biologic therapies, specialist clinicians, and other resources. In such patients, treatment may need to rely upon the available nonbiologic (traditional or conventional) disease-modifying antirheumatic drugs (DMARDs). We would take the following approach, assuming the availability of the nonbiologic, but not biologic, DMARDs:
●Initial therapy would not generally differ from patients with greater resources. (See "Initial treatment of mildly active rheumatoid arthritis in adults" and "Initial treatment of moderately to severely active rheumatoid arthritis in adults".).
●Triple therapy (with methotrexate [MTX], sulfasalazine [SSZ], and hydroxychloroquine [HCQ]) would be used in patients resistant to MTX alone. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Resistant to MTX' and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'DMARD triple therapy'.)
●Patients resistant to triple therapy can be treated with MTX plus leflunomide (LEF), with very close attention to monitoring of liver function tests. Unblinded studies have reported that the other combinations may also be effective alternatives, including MTX and azathioprine, as well as MTX, azathioprine, and HCQ [61] Patients intolerant of MTX may be treated with leflunomide (LEF) alone. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Leflunomide'.)
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 5^th to 6^th 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 10^th to 12^th 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 topics (see "Patient information: Rheumatoid arthritis (The Basics)" and "Patient information: Disease modifying antirheumatic drugs (DMARDs) (The Basics)")
●Beyond the Basics topics (see "Patient information: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient information: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Patients with rheumatoid arthritis (RA) benefit from the achievement and maintenance of tight control of disease activity, with the ideal goal of remission. Whenever possible, antiinflammatory agents, including glucocorticoids, should be used only as adjunctive agents. Patient education and other nonpharmacologic and preventive therapies, including appropriate immunizations, are needed for all patients with RA. (See 'General principles and approach' above.)
●In patients with RA, resistance to therapy with disease-modifying antirheumatic drugs (DMARDs) is defined as failure to achieve remission or low disease activity within three to six months despite the use of maximally tolerated doses within the usual therapeutic range; a need for excessively high doses of glucocorticoids in addition to DMARDs; or the occurrence of recurrent flares of disease requiring multiple courses of glucocorticoids with doses in excess of those acceptable for chronic therapy, despite maximally tolerated or acceptable doses of the DMARDs being used. (See 'Definition of resistance to DMARDs' above.)
●In patients who do not respond adequately to therapy with an initial tumor necrosis factor (TNF) inhibitor within three to six months, we suggest switching to a different TNF inhibitor, rather than to another class of biologic (Grade 2C). An alternative approach is switching to another biologic agent with a different mechanism of action in this setting rather than to a second TNF inhibitor, particularly in patients who discontinue the initial TNF inhibitor due to a severe adverse reaction or an inadequate primary response to treatment. (See 'Resistant to one TNF inhibitor' above.)
●In patients whose treatment regimen has changed, reevaluation may be required up to every four to eight weeks for the effectiveness of therapy and for the monitoring of possible drug toxicity. We assess and monitor disease activity using a quantitative composite measure at each assessment. Further management is dependent upon disease response. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Reevaluation and monitoring'.)
●In patients who do not respond adequately to the therapies above, including trials of MTX and trials of two TNF inhibitors, we suggest the use of abatacept, tocilizumab, or rituximab, rather than the administration of a third TNF inhibitor (Grade 2B). Tofacitinib is an alternative agent in such patients. Choice between these agents depends primarily upon patient preference; regulatory, insurance, and cost limitations; comorbidities; and clinician experience. (See 'Resistant to two TNF inhibitors' above.)
●We continue nonbiologic and biologic DMARD therapy at reduced doses or dose frequency, if possible, for patients in remission, rather than discontinuing treatment with DMARDs. (See "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Duration of therapy'.)
●In patients experiencing a disease flare that is not controlled with nonsteroidal antiinflammatory drugs (NSAIDs), we suggest treatment with intraarticular or oral glucocorticoids rather than switching or continuing NSAIDs as the only additional agent (Grade 2A). We use antiinflammatory drug therapy, including 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 a new DMARD regimen has taken effect. Some patients benefit from chronic low-dose glucocorticoid therapy (eg, prednisone to 5 to 7.5 mg daily). (See 'Symptomatic drug therapy' above and "Treatment of rheumatoid arthritis in adults resistant to initial nonbiologic DMARD therapy", section on 'Drug therapy for flares' and "General principles of management of rheumatoid arthritis in adults", section on 'Drug therapy for flares'.)