Approach

Early and aggressive treatment with conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs), potentially combined with a biological agent or a targeted synthetic DMARD, is recommended.[88]​ Rheumatoid arthritis (RA) is a cause of morbidity and mortality, and any delay in treatment contributes greatly to both.[88][89]​​​​​

Early diagnosis and treatment is associated with improved outcomes and is an important principle of management.[49] Presence of poor prognostic factors should alert the clinician that more aggressive therapy may be needed.

Hepatitis B and C status, purified protein derivative (PPD), full blood count (FBC), and liver function tests (LFTs) need to be checked before starting treatment.

FBC and LFTs should be monitored regularly during treatment.

Treat-to-target

Treat-to-target - involving frequent monitoring of disease activity using validated instruments, and the modification of treatment to minimise disease activity with the goal of reaching a predefined target - is recommended.[49]

An initial treatment target of low disease activity is recommended rather than a goal of remission, as established remission criteria may not be achievable for many patients.[49][62]​​[88]​​ See Diagnostic criteria for ACR/EULAR remission criteria.

Patients should be at target (low disease activity or remission) for at least 6 months prior to tapering of treatment.[49]

Tapering/discontinuing DMARDs

For patients at target for at least 6 months, the preferred option is to continue all DMARDs, rather than reducing the dose or gradual discontinuation of DMARD treatment.[49]

For patients taking combination therapy who wish to discontinue a DMARD, gradual discontinuation of methotrexate is recommended rather than gradual discontinuation of the biological agent or targeted synthetic DMARD.[49][90]​ One open-label randomised trial comparing half-dose conventional synthetic DMARD with stable-dose conventional synthetic DMARDs found that patients receiving half-dose conventional synthetic DMARD had significantly more disease flares than those on the stable dose.[91] However, subsequent systematic reviews demonstrated that tapering methotrexate from combination treatment with DMARDs treated at target may increase the risk of disease activity, compared with no tapering, but had limited effect on patients in established remission.[92][93]

Two systematic reviews concluded that reducing the dose or increasing time between DMARD treatments did not impact disease activity, the risk of serious adverse effects, malignancies, cardiovascular adverse effects, or death in patients with RA who have achieved remission.[94][95]

Conversely, an additional systematic review reported tapering tumour necrosis factor (TNF)-alpha inhibitors increased the risk of flare in people with RA in remission for more than one year.​​​​​[96]

One systematic review and meta-analysis suggests that for patients with low disease activity RA, tapering corticosteroids reduce time to flare compared with patients who did not taper corticosteroids.[97]​​

Sulfasalazine is the preferred option for gradual discontinuation among patients taking triple therapy (hydroxychloroquine, sulfasalazine, and either methotrexate or leflunomide).[49]

Low disease activity at initial presentation

In practice, patients with low disease activity are usually started on a single conventional synthetic DMARD (i.e., hydroxychloroquine, sulfasalazine, methotrexate, or leflunomide).[49][62][88]

The American College of Rheumatology and the National Institute of Health and Care Excellence (NICE) in the UK recommend first-line hydroxychloroquine treatment for patients with low disease activity, over other DMARDs.[49][62]​​ It is better tolerated and has a more favourable risk profile in patients with RA. Sulfasalazine is recommended over methotrexate as patients with low disease activity may wish to avoid the adverse effects associated with methotrexate therapy. Methotrexate is recommended over leflunomide due to its greater dosing flexibility.[49] Treatment with methotrexate has been demonstrated to significantly reduce overall mortality for patients with RA, including cardiovascular and interstitial lung disease mortality.[98]​​

Short-term corticosteroid treatment may be used for symptom control in patients with early disease, those with acute flare of disease activity, or those starting or changing DMARD treatment, but should be tapered and discontinued as quickly as clinically possible.[62][88][99] There is some evidence to suggest that there is an association between methotrexate dose and bacterial infections during treatment with biological agents in combination with corticosteroids in people with RA.[100]​​​​​

For patients taking a corticosteroid to remain at target, addition of, or switching to, a DMARD is preferred (as a corticosteroid-sparing measure) to continuation of the corticosteroid.[49]

Non-steroidal anti-inflammatory drugs (NSAIDs) can be used in patients with early disease or those with acute flares of disease activity.[62][99]​​ The lowest effective dose for the shortest effective duration should be used with appropriate preventative therapy (e.g., a proton-pump inhibitor).[62]

Moderate-to-severe disease activity at initial presentation

A more aggressive approach may be needed if the patient has:

  • Moderate-to-severe disease activity with or without extra-articular manifestations (e.g., pleuritis, interstitial lung disease, pericarditis, inflammatory eye disease) with poor prognostic factors, such as rheumatoid factor (RF) positivity and/or anti-cyclic citrullinated peptide (anti-CCP) antibodies, and

  • Radiographic evidence of bony erosions at presentation.

Conventional synthetic DMARDs

Methotrexate monotherapy is the initial treatment of choice for patients with moderate-to-severe disease activity.[49][88]​​

Evidence suggests that methotrexate administered subcutaneously is more effective than oral methotrexate. Oral administration is, however, preferred for patients initiating methotrexate, due to the ease of administration and similar bioavailability at typical starting doses.[49][101]

For patients who are not able to tolerate oral weekly methotrexate, a split dose of oral methotrexate over 24 hours or weekly subcutaneous injections, and/or an increased dose of folic acid, is recommended before switching to an alternative DMARD.[49]

If methotrexate cannot be used, then leflunomide, hydroxychloroquine, or sulfasalazine are alternatives.​[49][88]

No or inadequate response to conventional synthetic DMARD

If the patient does not respond or has an inadequate response to methotrexate monotherapy, a biological agent (e.g., TNF-alpha inhibitor, an interleukin 6 [IL-6] inhibitor, abatacept, or rituximab), or a targeted synthetic DMARD such as an oral Janus kinase (JAK) inhibitor, can be added to methotrexate, taking into account pertinent risk factors.[49][88]​​​[102][103][104][105][106][Evidence C]

One systematic review concluded that the combination of methotrexate with a biological agent does increase efficacy of treatment for people with RA compared with methotrexate treatment alone.[107] In absolute terms, 7 to 16 more people out of 100 may have increased overall likelihood of responding to treatment with combination therapy.​[107]

Combination therapy with methotrexate in addition to certolizumab pegol, abatacept, or tocilizumab is generally well tolerated in people with early RA at 24 weeks.[108] Adverse effects tend to increase at the target dose, and these were more frequent in combination with tocilizumab compared with active conventional treatment, which included either methotrexate plus an oral corticosteroid, or methotrexate plus sulfasalazine plus hydroxychloroquine plus intra-articular corticosteroids at 24 weeks.​[108]

Rarely, a biological agent or a targeted synthetic DMARD may be started as monotherapy, but the benefits and risks should be carefully considered for each individual patient before initiating treatment.

One systematic review suggests that patients with RA who smoke have an increased risk of having an inadequate response to methotrexate, especially DMARD naive patients with early RA.[109]

TNF-alpha inhibitors

TNF-alpha inhibitors (e.g., etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) have proven efficacy in placebo-controlled trials.​[110][111] [ Cochrane Clinical Answers logo ] One network meta-analysis reported that biological agents in combination with methotrexate (with the exception of golimumab) were associated with significantly lower rates of radiographic progression at 1 year compared with methotrexate alone.[112]

In the UK, adalimumab, etanercept, or infliximab, added to methotrexate, is recommended for adult patients with moderate RA (a disease activity score [DAS28] of 3.2 to 5.1) who have an inadequate response with two or more conventional synthetic DMARDs.[113] [ Cochrane Clinical Answers logo ]  Adalimumab and etanercept can be used as monotherapy for patients when methotrexate is contraindicated, or not tolerated, provided that the above criteria are met.[113]

TNF-alpha inhibitors have been associated with increased risk for serious infection (tuberculosis and other opportunistic infections) compared with synthetic DMARDs, and increased risk for treatment discontinuation.[114][115][116] [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ]

Lymphoma and other malignancies have been reported in patients treated with TNF-alpha inhibitors. However, systematic reviews and meta-analyses have not reported an increased risk of malignancy among patients with RA receiving TNF-alpha inhibitor therapy.[116][117][118][119][120][121]​​ When evaluating relevant systematic reviews and meta-analyses, consider that:[117][118]

  • Studies subject to meta-analysis have typically been of short duration and increased long-term risk of malignancy cannot, therefore, be excluded

  • Patients with a prior history of cancer may have been excluded from studies, making it difficult to extrapolate results to patients with a previous cancer.

Ongoing research seeks to establish the effect of specific DMARDs on risk of malignancy, particularly risk for non-melanoma skin cancer and melanoma.[122]

Potential adverse effects associated with TNF-alpha inhibitors can be minimised by using an individualised dose reduction/withdrawal strategy once disease control has been established. The results of two systematic reviews suggest that:[123][124]

  • Disease activity-guided dose tapering of TNF-alpha inhibitors is comparable to continuation of treatment with respect to the proportion of patients with persistent remission and may be comparable regarding disease activity

  • Discontinuation of TNF-alpha inhibitors is inferior to continuation of treatment with respect to disease activity, the proportion of participants with persistent remission, function, and minimal radiographic damage.

IL-6 inhibitors

Tocilizumab and sarilumab are approved for the treatment of adults with moderately to severely active RA who have had an inadequate response to one or more DMARDs.

They may be used as monotherapy, or in combination with methotrexate or other conventional synthetic DMARDs.[125][126][127]

Evidence from systematic reviews using indirect comparisons suggest that tocilizumab may be more effective than sarilumab for treating people with RA who inadequately respond to either methotrexate or TNF-alpha inhibitors.[128][129] An additional systematic review concluded that for people with RA with an inadequate response to conventional synthetic DMARDs, sarilumab monotherapy is more effective than adalimumab, biological agents, and targeted synthetic DMARDs.[130]​​​

One open-label randomised trial evaluated the efficacy and safety of increasing the dose interval of subcutaneous tocilizumab in patients with RA who are in remission.[131] The study reported that although most patients sustained remission with a half-dose of tocilizumab, increasing the dose interval to 2 weeks was associated with a lower likelihood of maintaining remission, with no improvement in tolerability.[131]

There is evidence to suggest that treatment with interleukin (IL) inhibitors, including IL-6 inhibitors, may increase the risk of serious infection, opportunistic infections, and cancer in patients with RA compared with placebo.[132] Tocilizumab has been associated with a drug-induced sarcoidosis-like reaction, occurring in temporal relationship with the initiation of tocilizumab, and a significant risk of the reactivation of hepatitis B virus (HBV) in people with RA and chronic HBV.[132][133][134][135]​​

The European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) identified serious hepatotoxicity (including acute liver failure, hepatitis, and jaundice) in eight patients treated with tocilizumab worldwide.[136][137] Two cases required liver transplantation. Serious liver injury has been reported from 2 weeks to >5 years after starting treatment. While liver toxicity occurs rarely, and the risk-benefit profile still supports the use of tocilizumab, the MHRA recommends monitoring alanine aminotransferase (ALT) or aspartate aminotransferase (AST) at initiation of treatment, every 4-8 weeks for the first 6 months of treatment, and then every 12 weeks thereafter. Be cautious when considering starting tocilizumab treatment in patients with ALT or AST levels higher than 1.5 times the upper limit of normal (ULN). Tocilizumab is not recommended if ALT or AST levels are higher than 5 times the ULN. If liver enzyme abnormalities are identified, dose modification should be considered (reduction, interruption, or discontinuation) according to the manufacturer's recommendations. Advise patients to seek medical help immediately if they experience signs and symptoms of hepatic injury.[137]

Abatacept

Abatacept is approved for the treatment of moderately to severely active RA. It has similar safety and efficacy to the TNF-alpha inhibitors, and is indicated in patients who have an inadequate response to methotrexate.[138][139] [ Cochrane Clinical Answers logo ] Abatacept or adalimumab given subcutaneously with background methotrexate (as would usually be the case in clinical practice) have been shown to have similar efficacy, safety, and time to response in patients with active RA who were naive to biological agents and who had an inadequate response to methotrexate.[139]

Evidence suggests that abatacept, as monotherapy or in combination with methotrexate, provides more effective disease control compared with conventional treatment (methotrexate with corticosteroids), methotrexate alone, or biological agents or targeted synthetic DMARDs in patients with RA.[140][141][142] [ Cochrane Clinical Answers logo ] ​ There is evidence demonstrating sustained remission with abatacept following dose reduction.[143] Few patients sustain a major response 1 year after withdrawal of abatacept therapy; re-treatment with abatacept plus methotrexate may be effective in this setting.[144]

Abatacept is recommended over other biological agents and targeted synthetic DMARDs for patients with non-tuberculous mycobacterial lung disease who have moderate-to-high disease activity despite conventional synthetic DMARDs.[49]

Rituximab

Rituximab is a B-cell modulator approved for use in combination with methotrexate for the treatment of adults with moderate to severely active RA who have had an inadequate response to one or more TNF-alpha inhibitors.[49]

Rituximab is recommended over other DMARDs, regardless of previous DMARD experience, for patients who have a previous lymphoproliferative disorder (for which rituximab is an approved treatment), and who have moderate-to-high disease activity, because it would not be expected to increase the risk of recurrence or worsening of lymphoproliferative disorders.[49]

In the setting of persistent hypogammaglobulinaemia without infection, continuation of rituximab therapy for patients at target is conditionally recommended over switching to a different biological agent or targeted synthetic DMARD.[49] Continuing rituximab in patients who are at target is preferred due to the uncertain clinical significance of hypogammaglobulinaemia in patients without infection. Although an increased risk of infection has been described in RA patients with hypogammaglobulinaemia, it is not known if a switch in DMARDs in patients who are at target is more effective in lowering infection risk while maintaining disease control than continuation of rituximab. 

Targeted synthetic DMARDs

Targeted synthetic DMARDs include the oral Janus kinase (JAK) inhibitors tofacitinib, baricitinib, and upadacitinib, which are all approved to treat moderate to severely active RA.[49] Filgotinib, another selective inhibitor of JAK1, is approved in Europe and the UK for the treatment of moderate to severely active rheumatoid arthritis in adults who have responded inadequately to, or who are intolerant to, one or more DMARDs.

The US Food and Drug Administration (FDA) has issued a warning about an increased risk of serious cardiovascular events, malignancy, thrombosis, and death with tofacitinib, baricitinib, and upadacitinib.[145] This follows final results from a large randomised safety clinical trial comparing tofacitinib with tumour necrosis factor (TNF)-alpha inhibitors in patients with RA. The study found an increased risk of blood clots and death with the lower dose of tofacitinib (5 mg twice daily); this serious event had previously been reported only with the higher dose (10 mg twice daily) in the preliminary analysis.[146]

The FDA advises clinicians to:[145] 

  • Reserve tofacitinib, baricitinib, and upadacitinib for patients who have had an inadequate response or are intolerant to one or more TNF-alpha inhibitors

  • Consider the patient’s individual benefit-risk profile when deciding to prescribe or continue treatment with these medications, particularly in patients who are current or past smokers, patients with other cardiovascular risk factors, those who develop a malignancy, and those with a known malignancy (other than a successfully treated non-melanoma skin cancer).

The European Medicines Agency (EMA) has also recommended measures to minimise the risk of serious adverse effects with JAK inhibitors. The EMA advice relates to patients aged >65 years, those who are current or past smokers, patients with other cardiovascular risk factors (such as heart attack or stroke), and patients with other malignancy risk factors. In these patient groups, JAK inhibitors should only be used to treat moderate or severely active RA, if no suitable treatment alternative is available.[147]​​​​

The EMA recommends that JAK inhibitors should be used with caution in patients with risk factors for blood clots in the lungs and in deep veins (venous thromboembolism, VTE); and that doses should be reduced in patient groups who are at risk of VTE, cancer, or major cardiovascular problems, if possible. This recommendation is based on one observational study comparing the safety of baricitinib with TNF-alpha inhibitors.​[147][148]

In the UK, the National Institute for Health and Care Excellence (NICE) has recommended filgotinib (a JAK1 inhibitor) in combination with methotrexate as an option for adult patients with moderate to severe RA (i.e., a disease activity score [DAS28] of 3.2 or more) who have an inadequate response to intensive therapy with two or more conventional synthetic DMARDs.[149]

For severe disease (DAS28 of more than 5.1) NICE recommend filgotinib with methotrexate as an option if the patient:[149]

  • Cannot tolerate rituximab, and has responded inadequately to or cannot have other DMARDs, including at least one biological DMARD

  • Has an inadequate response to rituximab and at least one biological DMARD.

Filgotinib can be used as monotherapy in a patient with a contraindication to or intolerance of methotrexate when the above criteria are met.[149][150] 

Corticosteroids

Although DMARD therapy is the preferred initial treatment for patients with moderate to severely active RA, corticosteroids are commonly used in combination with a first-line DMARD, particularly for patients with early RA starting or changing DMARD treatment, and for patients with disease flare.[49][88]​​[99]​ In addition to working faster than most DMARDs, corticosteroids also have some disease-modifying effect, which contributes to overall disease control.[67][151][152][153][154][155][156]

Corticosteroid treatment usually involves low-dose daily oral prednisolone; doses >10 mg/day are rarely required. However, there is evidence to suggest that high- or moderate-dose prednisolone tapered to a low dose is effective for remission induction when combined with methotrexate in patients with early RA and poor prognostic markers.[157] Corticosteroid doses as low as 2.5 mg/day have been associated with BMD loss in people with inflammatory rheumatic disease, but is preventable with the use of medicines for osteoporosis prophylaxis.[158] See Osteoporosis. Low dose corticosteroids have been demonstrated to increase weight by approximately 1 kg after two years of treatment.[159]​​​

In one double-blind trial, adults with RA receiving tocilizumab and corticosteroids for 24 weeks were randomised either to continue masked prednisolone for 24 weeks or to taper masked prednisolone by week 16.[160] In all patients assigned to the continued prednisolone regimen, disease activity control was superior compared with patients assigned to the tapered prednisolone regimen.

A delayed-release formulation of low-dose oral prednisolone may have a role in RA when used as an adjunct to DMARDs.[161]

Patients can be treated with intramuscular corticosteroids as needed in addition to DMARD therapy, especially early in disease when rapid symptom relief may be desired while patients are waiting for DMARDs to start working.

Intra-articular corticosteroid injections are used to control individually inflamed joints in acute flares of disease activity.

If corticosteroids are given daily, calcium and vitamin D supplementation and yearly to biannual bone density assessment are recommended. However, some evidence suggests that suppression of inflammation by corticosteroids may counterbalance their adverse effects on bone remodelling up to 24 months in patients with early RA.[162]

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs can be used for symptom control in patients with early disease or those with acute flare of disease activity.[62][99] The lowest effective dose for the shortest effective duration should be used.[62]

Failure to reach low disease activity after 3 months

Patients are usually re-assessed at 3 months or less using the same disease activity measure employed during diagnosis/initial treatment visit. This will objectively document improvement (or lack of) and determine the next step in the treatment plan.

A small percentage (2.7%) of people with RA may present with poly-refractory RA defined as failure of all biological agents and targeted synthetic DMARDs.[163]

First-line options

Combination therapy with methotrexate and either a biological agent or a targeted synthetic DMARD is recommended first line for these patients.[49][88]​​

For patients taking weekly oral methotrexate who are not at target, switching to subcutaneous methotrexate is recommended over addition of/switching to alternative DMARD(s).[49]

A combination of methotrexate plus a TNF-alpha inhibitor has been shown to be more effective in patients with high disease activity than either methotrexate or a TNF-alpha inhibitor alone.[102][164][165][166] One systematic review and network meta-analysis reported only minor differences in efficacy between biological treatments, in combination with methotrexate, among RA patients after methotrexate failure.[167] All have proven efficacy in placebo-controlled trials.[111][167]​​ [ Cochrane Clinical Answers logo ]

For patients on combination therapy not at target, switching to a biological agent or targeted synthetic DMARD of a different class is recommended, although evidence for this approach is unclear.[49][88]​​[168][169]

There are data to suggest that switching to tocilizumab or JAK inhibitor monotherapy may be as effective as combination tocilizumab plus methotrexate in some RA patients with an inadequate response to methotrexate.[170][171] However, more long-term data and studies in methotrexate-naive patients are needed to confirm these findings.

One prospective cohort study reported that among adults with refractory RA (inadequate response to a TNF-alpha inhibitor), rituximab and tocilizumab are associated with greater improvements in outcomes at 24 months (survival without drug failure, good or moderate EULAR response) compared with abatacept.[172]

A corticosteroid and/or NSAID may be used for symptom control in patients with early disease or those with acute flare of disease activity.[99]

Second-line options

Triple therapy with synthetic DMARDs (e.g., methotrexate plus hydroxychloroquine plus sulfasalazine) may be a second-line option in select patients who fail to reach low disease activity after 3 months.[62]​ However, this regimen is rarely used now that biological agents/targeted synthetic DMARDs are available, and it is not recommended by US guidelines.[49]

In a prospective study of RA patients registered on the nationwide Swedish Rheumatology Quality Register, the likelihood of reaching sustained remission was higher with biological therapy (a biological agent plus methotrexate) than with triple therapy.[173] For specific RA patients, however, triple therapy was believed to be an alternative to biological therapy without prejudicing future likelihood of sustained remission.

Evidence from one systematic review suggests that treatment with biological agents seems to be more effective compared with triple DMARD therapy in terms of radiological progression in RA with inadequate response to methotrexate.[174]

A corticosteroid and/or NSAID may be used for symptom control in patients with early disease or those with acute flare of disease activity.[99]

Pregnant patients

Most medicines used to treat RA cannot be used while a patient is pregnant or planning a pregnancy; however, symptoms of RA usually diminish during pregnancy.[175]

Corticosteroids are considered the safest option for patients who are planning pregnancy or who are pregnant, although sulfasalazine or hydroxychloroquine can also be used. There is a lack of human data for use of sulfasalazine and hydroxychloroquine in pregnancy, so these agents are only recommended if corticosteroids are not an option, and only under a specialist with experience of treating pregnant women.

Biological agents and JAK inhibitors are generally not recommended in pregnancy due to a lack of safety data; some agents may be considered if the benefits outweigh the risks to the mother and fetus. There are data to suggest that certolizumab may be an option in pregnancy due to a lack of placental transfer.[176] A specialist should be consulted for guidance on using these drugs in pregnant women.

FBC and LFTs need to be checked before starting sulfasalazine or hydroxychloroquine and should be monitored every 4-8 weeks at the start of treatment. When the patient is on a stable dose, monitoring can be done every 3-4 months.

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