Rheumatoid Arthritis (RA) Treatment & Management

Optimal care of patients with rheumatoid arthritis (RA) consists of an integrated approach that includes both pharmacologic and nonpharmacologic therapies. Many nonpharmacologic treatments are available for this disease, including exercise, diet, massage, counseling, stress reduction, physical therapy, and surgery. Active participation of the patient and family in the design and implementation of the therapeutic program helps boost morale and ensure compliance, as does explaining the rationale for the therapies used.

Medication-based therapies comprise several classes of agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs), and corticosteroids. Early therapy with DMARDs has become the standard of care, because it can both retard disease progression more efficiently than later treatment and, potentially, induce more remissions. ^{[73, 74, 75]}

A treat-to-target approach is recommended for RA, with the target being low disease activity or remission, as determined by validated instruments for measuring disease activity (see Workup/Measures of Disease Activity). ^{[5, 4]} Online calculators are available for the following RA disease activity measures:

• Clinical Disease Activity Index for RA (CDAI)
• DAS28-CRP for Rheumatoid Arthritis
• DAS28-ESR for Rheumatoid Arthritis
• Simplified Disease Activity Index for RA (SDAI)

In pregnant patients with RA, no special obstetric monitoring is indicated beyond what is performed for usual obstetric care. However, some of the medications used in treating RA can have adverse effects on the fetus and may have to be discontinued several months before conception is planned.

Surgical procedures used in the treatment of RA include the following:

• Synovectomy
• Tenosynovectomy
• Tendon realignment
• Reconstructive surgery or arthroplasty
• Arthrodesis

Once a diagnosis of RA is made, the main treatment goals are to control disease activity and slow the rate of joint damage, in addition to minimizing pain, stiffness, inflammation, and complications. Pharmacologic therapies that are used include nonbiologic and biologic DMARDs and adjunctive agents such as corticosteroids, NSAIDs, and analgesics.

A study by Callhoff et al found that biologic agents were significantly more effective than nonbiologic treatments in improving physical function in RA. The meta-analysis of 35 studies that included 8733 treated patients with RA and 4664 controls determined that more than 50% of patients treated with biologics experienced clinically relevant improvement. Etanercept and rituximab were the most effective treatments, both in patients who had never before taken antirheumatic drugs and in those who had shown an inadequate response to them. ^[76]

The immunosuppressive effects of DMARDs place patients with RA at greater risk of infection and of more serious complications of infection. ACR guidelines provide recommendations on vaccinations in children and adults with RA or other rheumatic and musculoskeletal diseases, including RA, including guidance on coordination of immunosuppressive medication use with vaccination scheduling. ^[77]

Early DMARD therapy

DMARDs can be classified into nonbiologic and biologic agents. The nonbiologic DMARDs include the following:

• Hydroxychloroquine (HCQ)
• Azathioprine (AZA)
• Sulfasalazine (SSZ)
• Methotrexate (MTX)
• Leflunomide
• Cyclosporine
• Gold salts
• D-penicillamine
• Minocycline

The recognition of tumor necrosis factor–α (TNF-α) and interleukin (IL)-1 as central proinflammatory cytokines has led to the development of biologic agents that block these cytokines or their effects. In addition to improving signs and symptoms and quality of life, all biologic agents significantly retard radiographic progression of joint erosions. Biologic DMARDs include agents such as adalimumab, certolizumab, etanercept, golimumab, and infliximab.

DMARDs represent the most important measure in the successful treatment of RA. These agents can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function. Successful DMARD therapy may eliminate the need for other anti-inflammatory or analgesic medications; however, until the full action of DMARDs takes effect, anti-inflammatory or analgesic medications may be used as bridging therapy to reduce pain and swelling.

Many studies have revealed that early treatment of RA (ie, within months of onset) with DMARDs not only can retard disease progression more efficiently than later treatment but also may induce more remissions. ^{[73, 74, 75]} Thus, early DMARD therapy (< 6 months after the onset of symptoms) has become the standard of care. ^[78] Patients with early forms of arthritis should be evaluated by and, if necessary, referred to physicians who are experienced in the diagnosis and treatment of RA.

Nonbiologic DMARDs

In terms of frequency of remissions and time to onset of action, MTX and SSZ are the most active compounds and provide the best risk-benefit ratios. MTX, either alone or in combination with other agents, has become the standard of care for moderate to severe RA. ^{[5, 4]}

In 2013, the US Food and Drug Administration (FDA) approved the first single-dose, self-administered, disposable MTX subcutaneous autoinjector (Otrexup). ^[79] Otrexup is indicated for adults with severe, active RA who have either responded inadequately to or cannot tolerate first-line therapy, as well as for children with active polyarticular juvenile idiopathic arthritis (JIA) (also known as juvenile rheumatoid arthritis). ^[79]

Triple therapy—MTX, SSZ, and HCQ—may provide greater improvement in disease activity compared with MTX monotherapy, but has the disadvantages of less convenience and greater cost. ^[4] In a meta-analysis of 158 trials, triple therapy was found to have a statistically significant benefit of inhibiting joint damage compared with oral MTX alone. Also, there was no statistically significant difference in prevention of joint damage between triple therapy and MTX in combination with a biologic (adalimumab, certolizumab, etancercept, or inflximab) or the combination of MTX and tofacitinib. ^[80]

The results of a retrospective cohort study found that the use of HCQ may decrease the risk of diabetes in patients with RA. Further studies are needed to determine its preventive role in other patients at high risk for diabetes. ^[81] The results of a retrospective cohort study involving 121,280 patients found a lower adjusted risk of diabetes mellitus among individuals with RA or psoriasis who started a TNF inhibitor or HCQ than among those taking other nonbiologic DMARDs. ^[82]

A multinational retrospective study that compared new use of HCQ (n=956,374) with new use of SSZ (n=310,350) in adults with RA found no excess risk of severe adverse events with either drug over the first 30 days of therapy. With long-term use, however, HCQ appeared to be associated with higher cardiovascular mortality (calibrated hazard ratio [HR] 1.65; 95% confidence index [CI] 1.12–2.44]). ^[83]

Leflunomide is the most recent addition to the nonbiologic DMARDs and has activity similar to that of SSZ and MTX. It may be used in patients with contraindications to, or intolerance of, MTX. ^[5]

Minocycline may act as a DMARD through its action as a matrix metalloproteinase inhibitor (MMPI). Injectable gold salts and penicillamine rarely induce sustained remission and thus have largely been supplanted by more effective agents.

Biologic DMARDs: TNF inhibitors

The TNF inhibitors, which bind TNF and thus prevent its interaction with its receptors, include the following:

• Etanercept
• Infliximab
• Adalimumab
• Certolizumab
• Golimumab

Precautions and adverse effects

Biologic agents are expensive. Consensus statements do not recommend their use until at least one nonbiologic DMARD, usually MTX, has been administered without sufficient success. In clinical trials, as many as 70% of patients achieve significant responses, but remissions are not usually observed. ^[84]

Adverse effects associated with the biologic agents include the generation of antibodies against these compounds, emergence of antinuclear antibodies (ANAs), occasional drug-induced lupuslike syndromes, and infections (including tuberculosis). Rarely, demyelinating disorders and bone marrow suppression occur. Immunogenicity, such as the development of anti-drug antibodies, has been shown to occur with adalimumab and infliximab, potentially leading to decreased drug efficacy. Concomitant use of MTX may reduce the frequency of anti-drug antibody development. ^[85]

Acute and chronic infections, demyelinating disorders, class III or IV heart failure, and recent malignancies are contraindications to the use of TNF inhibitors. Thoroughly searching for latent tuberculosis using purified protein derivative (PPD) testing or an interferon (IFN) gamma release assay (IGRA), with or without chest radiography, is recommended before these agents are started.

Patients taking anti-TNF agents must avoid live-virus vaccines. Giving live vaccines to patients receiving immunosuppressive drugs leads to a higher risk for serious infection.

The results of one study noted that the use of anti-TNF therapy may double the risk of septic arthritis in patients with RA, with the risk being highest in the early months of therapy. Although not significantly influenced by anti-TNF therapy, previous joint replacement surgery was also noted as a risk factor for septic arthritis. ^[86]

Hepatitis B virus (HBV) reactivation can occur in both hepatitis B surface antigen (HBsAg)–positive and HBsAg-negative/hepatitis B core antibody (anti-HBc)-positive patients with detectable occult HBV infection during anti−TNF-α therapy. Antiviral prophylaxis may effectively reduce this reactivation. ^[87]

In three Swedish registries that analyzed the cancer risk in 6366 RA patients taking TNF inhibitors, no increased risk of cancer with these agents was observed. ^[88] These patients were compared with 61,160 biologics-naive RA patients, 5989 patients starting MTX, 1838 patients starting DMARD combination therapy, and the general Swedish population. Of patients taking TNF inhibitors, 240 developed first-time cancer, yielding a relative risk (RR) of 1.00 compared with the biologics-naive cohort. Similar RRs were shown with the other cohorts.

TNF inhibitors versus MTX

In one study, bone erosions showed a higher rate of repair in RA patients treated with TNF inhibitors than in patients treated with MTX. ^[89] After a 1-year follow-up, bone erosions in the group treated with TNF blockers showed a mean width of 2 mm and a mean depth of 2.3 mm; the MTX-treated group showed a mean width of 2.4 mm and a mean depth of 2.4 mm. Deeper lesions in the TNF-inhibitor group were also particularly prone to repair when compared with more shallow lesions. ^[89]

Van Vollenhoven et al reported that in patients with early RA who have MTX-treatment failure, the addition of a TNF antagonist was superior to the addition of conventional DMARDs. ^[90] In this study, 258 patients with early RA who did not achieve low disease activity after 3-4 months of MTX (up to 20 mg/wk) were randomized to receive additional treatment (in addition to MTX)  with SSZ and HCQ or with infliximab.

In the SSZ and HCQ group, 32 of 130 (25%) achieved the primary outcome, defined as a good response according to the European Alliance of Associations for Rheumatology (EULAR); in the infliximab group, 50 of 128 (39%) attained the primary outcome. ^[90]

A systematic review by Visser et al suggested that an initial oral MTX dose of 15 mg/wk, with escalation of 5 mg/mo to achieve target doses of 25-30 mg/wk or maximum tolerable doses, was the optimal evidence-based dosing strategy. ^[91] Starting at higher initial doses or escalating too rapidly may be limited by toxicity. Conversion from oral to subcutaneous (SC) administration of MTX is suggested for patients who have an inadequate response to oral therapy.

Adalimumab

The TNF-α inhibitor adalimumab is approved for use as monotherapy or in combination with MTX or other nonbiologic DMARDs. A double-blind controlled 52-week trial in 619 patients with active RA who had an incomplete response to MTX found that the addition of adalimumab provided better disease control than placebo. In an open-label extension study, patients in the original placebo arm who were switched to adalimumab experienced inferior radiographic, functional, and clinical outcomes after 5 years, compared with the patients in the original adalimumab arm, thus demonstrating the disadvantage of delaying anti-TNF therapy. ^[92]

According to data from a study of 221 consecutive RA patients, adalimumab blood levels of 5 to 8 μg/mL have the greatest effect on disease activity. In the study, adalimumab trough levels greater than 8 μg/mL had no additional beneficial effect on disease activity ^[93] Study participants were treated with 40 mg adalimumab subcutaneously every other week for 28 weeks and stratified according to whether or not they were taking concomitant MTX. Patients treated with concomitant MTX reached recommended blood levels at lower adalimumab doses. At 28-week follow-up, mean adalimumab levels were 4.1 μg/mL in patients receiving monotherapy and 7.4 μg/mL in patients receiving concomitant MTX. ^[93] MTX might contribute to increasing adalimumab blood levels by reducing inflammation and lowering the number of binding targets for adalimumab.

Certolizumab

Fleischmann et al found that monotherapy with certolizumab effectively reduced the signs and symptoms of active RA in patients in whom DMARD therapy had failed. ^[94] In this study, 200 patients were randomized on a 1:1 basis to receive certolizumab 400 mg or placebo every 4 weeks for 24 weeks. At 24 weeks, 45.5% of the certolizumab group achieved a 20% improvement, according to ACR criteria, compared with 9.3% of the placebo group. Statistically significant differences were observed as early as week 1 through week 24. ^[94]

A study by Smolen et al found that certolizumab plus MTX was more efficacious than placebo plus MTX, rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression. ^[95] In this study, 619 patients were randomized to receive certolizumab 400 mg at weeks 0, 2, and 4, followed by 200 mg or 400 mg plus MTX every 2 weeks or placebo plus MTX every 2 weeks.

Significantly more patients who received certolizumab 200 mg (57.3%) or 400 mg (57.6%) achieved 20% improvement by ACR criteria than did those who received placebo (8.7%). ^[95] Radiographic progression was significantly inhibited with certolizumab 200 mg or 400 mg, as compared with placebo. When compared with placebo plus MTX, certolizumab plus MTX significantly relieved signs and symptoms, improved physical function, and inhibited radiographic progression in patients with RA. ^[95]

Golimumab

Golimumab is a human anti−TNF-α monoclonal antibody that inhibits TNF-α bioactivity, thereby modulating immune activity in patients with RA. Using a modified intention-to-treat analysis, researchers demonstrated that golimumab plus MTX is more efficacious than MTX alone (and that golimumab alone is about as efficacious as MTX alone) in reducing disease signs and symptoms in MTX-naive patients. ^[96]

In this 52-week, randomized, double-blind, placebo-controlled study, which was was followed by an open-label extension through 5 years, 637 patients were randomized to receive placebo plus MTX (group 1), golimumab 100 mg subcutaneously (SC) plus placebo (group 2), golimumab 50 mg SC plus MTX (group 3), or golimumab 100 mg SC plus MTX (group 4). ^[96] Intent-to-treat analysis showed no significant differences in the primary endpoint between group 1 and groups 3 and 4 combined, indicating efficacy of subcutaneous golimumab. The incidence of serious adverse events was similar across all groups.

In 2013, the FDA approved golimumab for intravenous (IV) use. ^{[97, 98, 99]} Approval was supported by a phase 3 study of 592 patients with moderately to severely active RA who had been receiving background MTX for at least 3 months.

In this study, 58.5% (n = 231/395) of patients receiving treatment with golimumab IV plus MTX experienced significant improvements in signs and symptoms at week 14 compared with 24.9% of patients receiving placebo plus MTX (n = 49/197). ^[99] Improvement was demonstrated by at least a 20% increase in ACR 20 score, the study’s primary endpoint. A higher proportion of patients receiving golimumab plus methotrexate achieved at least a 50% improvement in ACR criteria (ACR 50) at week 14 (30%) compared with patients receiving placebo plus MTX (9%).

The rate of adverse events and serious adverse events, respectively, at week 24 were 53% and 4% in the golimumab group and 49% and 2% in the placebo group. ^{[97, 98]} The most common adverse events were "infections and infestations," including upper respiratory tract infection (> 5% of patients), urinary tract infection, and nasopharyngitis. Exacerbation of RA occurred in 5.6% of patients receiving placebo plus MTX. ^[97]

At week 52, the rate of adverse events and serious adverse events in the golimumab group were 65% and 9%, respectively. ^[97] No serious opportunistic infections occurred through week 52. However, in the golimumab group, a single case of tuberculosis was reported, and a patient died from a myocardial infarction secondary to community-acquired pneumonia. ^[97]

Biologic DMARDs: non-TNF agents

Rituximab

Rituximab is most often used in combination with MTX. It has been shown to be effective for reducing signs and symptoms in adult patients with moderately to severely active RA who have had an inadequate response to therapy with one or more TNF inhibitors. ^{[100, 101, 102]} The ORBIT study in 295 biological-treatment naive patients with RA found that initial treatment with rituximab is noninferior to initial TNF inhibitor treatment, and is cost saving over 12 months. ^[103]

Treatment with rituximab may deplete CD20+ B cells. A study by Bingham et al suggested that polysaccharide and primary immunizations should be administered before rituximab infusions in order to maximize immunization responses. ^[104] After administration of pneumococcal polysaccharide vaccine, a 2-fold rise in titers against 1 or more pneumococcal serotypes occurred in 57% of RA patients receiving rituximab and MTX, but in 82% of those receiving MTX alone.

Decreased response to a neoantigen (keyhole limpet hemocyanin [KLH]) was also seen in the rituximab-treated patients (47% vs 93%). ^[104] However, the ability to maintain a positive delayed-type hypersensitivity to a Candida albicans skin test was comparable in both treatment groups, as was response to tetanus toxoid.

Anakinra

Anakinra is a recombinant nonglycosylated form of the human IL-1 receptor antagonist (IL-1ra). IL-1ra occupies the IL-1 receptor without triggering it and prevents receptor binding of IL-1. In clinical trials, patients treated with anakinra were significantly more likely to demonstrate a American College of Rheumatology 20% improvement response (ACR20), compared with those receiving placebo. ^[105]

Abatacept

Abatacept is a selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CD86, thereby blocking their interaction with CD28. CD28 interaction provides a signal needed for the full T-cell activation that is implicated in RA pathogenesis.

Maintenance doses of abatacept may be administered as a monthly intravenous (IV) infusion or by the patient as a weekly SC injection. ^[106] In patients with RA who have previously had treatment failure with anti-TNF therapy, abatacept has been shown to demonstrate consistent safety and efficacy that are maintained from 6 months to 5 years of therapy. ^[107]

A head-to-head phase IIIb randomized noninferiority trial found that SC abatacept and SC adalimumab were equally effective in RA patients, with comparable safety (though adalimumab was associated with more injection-site reactions). ^[108] Adding either treatment to background methotrexate produced similar ACR20 rates and similar rates of radiographic nonprogression. In view of these findings, clinicians may reasonably conclude that the 2 agents are substantially equivalent for treating RA.

Tocilizumab

Tocilizumab, an IL-6 receptor inhibitor, is available as either an IV infusion or SC injection. It is indicated for moderate-to-severe active RA in adults who have had an inadequate response to 1 or more TNF-antagonist therapies. It may be used either alone or in combination with MTX or other DMARDs. However, Dougados et al found that in patients with active RA, combination therapy with IV tocilizumab and MTX did not yield better clinical results than tocilizumab monotherapy and combination therapy was more often associated with transaminase increases. ^[109]

In patients with inadequate response to TNF inhibitors, tocilizumab treatment results in significant, clinically meaningful, rapid, and sustained improvements in a number of patient-reported outcomes. ^{[110, 111]} A 2012 consensus statement confirmed the efficacy and safety of IL-6 pathway blockade in adult rheumatoid arthritis. ^[112]

In 2013, the FDA approved an SC injection of tocilizumab that can be self-administered after proper training. The SC formulation has been shown to be as effective as the IV infusion and has the same safety profile, except for increased injection site reactions with SC administration. ^[111]

Sarilumab

Also an IL-6 inhibitor, sarilumab is a human monoclonal antibody that binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R). It is approved for adults with RA who have had an inadequate response or intolerance to one or more DMARDs. Administration is by SC injection every 2 weeks. Sarilumab may be prescribed as monotherapy or with MTX or other conventional DMARDs.

Approval of sarilumab was based on the MOBILITY and TARGET trials. In the MOBILITY study, patients treated with sarilumab plus MTX had reduced signs and symptoms and improved physical function, and demonstrated significantly less radiographic progression of structural damage, compared with placebo plus MTX. At 24 weeks of treatment, the ACR20 score was 66% for sarilumab 200 mg, 58% for sarilumab 150 mg, and 33% for placebo. ^[113]

The TARGET study combined sarilumab with a DMARD. Results showed reduced signs and symptoms and improved physical function compared with placebo plus DMARD. Results were similar to the MOBILITY trial. At 24 weeks, ACR20 was 61% for sarilumab 200 mg, 56% for sarilumab 150 mg, and 34% for placebo. ^[114]

Tofacitinib

Janus kinases (JAKs) consist of a group of intracellular tyrosine kinases that transmit signals from cytokine or growth factor–receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs), which modulate intracellular activity, including gene expression.

JAK inhibitors modulate the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. These signals maintain the inflammatory condition in RA. Inhibition of JAKs reduces production of and modulates proinflammatory cytokines central to RA.

Tofacitinib is an oral JAK inhibitor ^[115] that was approved by the FDA in 2012 as second-line treatment for moderate to severe active RA. ^[116] The indication is specific for patients who have had an inadequate response to or are intolerant of MTX. Tofacitinib may be given as monotherapy or in combination with MTX or other nonbiologic DMARDs. It should not be used in combination with biologic DMARDs or potent immunosuppressive agents (eg, azathioprine or cyclosporine).

Tofacitinib has been associated with reductions in signs and symptoms of RA and improvement in physical function. ^[117] Fleischmann et al demonstrated that ACR criteria for a 20% response were met in 59.8% of patients receiving monotherapy with tofacitinib 5 mg twice daily, compared with 26.7% of patients receiving placebo. ^[118] Health Assessment Questionnaire Disability Index (HAQ-DI) reduction was also greater in the tofacitinib group (−0.50 points) than in the placebo group (−0.19 points).

In another study, in which 717 patients who received stable MTX doses over 12 months were randomized to also receive 5 mg or 10 mg of tofacitinib orally twice daily, adalimumab 40 mg every 2 weeks, or placebo, ACR 20% response rates at 6 months were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%). ^[119]

A once-daily 11-mg extended-release dosage form was approved by the FDA in 2016 as an alternative to the 5-mg twice-daily regimen.

However, a randomized trial by Ytterberg et al found that although the efficacy of tofacitinib is similar to that of TNF inhibitors, risks of major adverse cardiovascular events, cancers, and certain opportunistic infections (eg, herpes zoster, tuberculosis) were higher with tofacitinib. ^[120]

The trial compared tofacitinib at a dose of 5 mg twice daily (n=1455) or 10 mg twice daily (n=1456) with a TNF inhibitor (n=1451) in patients with active RA despite MTX treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor. Incidence rates of major adverse cardiovascular events with the combined tofacitinib doses versus a TNF inhibitor were 3.4% vs 2.5%, respectively (hazard ratio [HR], 1.33], while rates of cancers were 4.2% versus 2.9%, respectively (HR 1.48) for cancers. ^[120]

Baricitinib

The FDA approved a second JAK inhibitor, baricitinib (Olumiant), in 2018 as a second-line treatment of moderately to severely active RA in adults who have had an inadequate response to one or more TNF antagonists. Baricitinib may be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs. It should not be used in combination with biologic DMARDs or potent immunosuppressive agents (eg, azathioprine or cyclosporine).

The dosage of baricitinib is one 2-mg tablet daily. The FDA declined to approve 4-mg tablets, citing safety concerns. The drug's prescribing information will contain a boxed warning about the risk for serious infections, malignancies, and thrombosis. ^[121]

Approval of baricitinib was supported by the RA-BUILD, RA-BEYOND, and RA-BEACON phase III clinical trials. The RA-BUILD study was a double-blind 24-week study that included 684 biologic DMARD–naïve patients with RA and inadequate response or intolerance to 1 or more conventional synthetic DMARDs. At week 12, 62% of patients taking baricitinib 4 mg achieved ACR20 response, compared with 39% of those taking placebo (P ≤0.001). ^[122]

In the RA-BEYOND study,  radiographic progression at 24 and 48 weeks was statistically significantly lower for either baricitinib 2 or 4 mg compared with placebo. However, only baricitinib 4 mg demonstrated statistically significant inhibition of progressive radiographic joint damage compared with patients initially randomized to placebo when observed at week 48. ^[123]

In the RA-BEACON study (n=527), patients with RA received baricitinib 2 mg, baricitinib 4 mg, or placebo in addition to conventional DMARDs they were currently taking. Patients in the study had demonstrated an inadequate response or intolerance to at least one TNF inhibitor therapy. Study participants could have undergone prior therapy with other biological DMARDs. At week 12, patients taking baricitinib had significantly higher ACR20 response rates (49%, versus 27% for placebo) and gains in all individual ACR20 component scores. ^[124]

Upadacitinib 

Another JAK inhibitor, upadacitinib, was approved in 2019 for moderately to severely active RA in adults who have had an inadequate response or are intolerant to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiological DMARDs.

Approval was based on data from the SELECT phase 3 RA program that enrolled over 4000 patients with moderate to severe RA across 5 studies. In the SELECT-MONOTHERAPY study, 598 or 648 patients completed the study. At week 14, an ACR20 response was achieved by 89 (41%) of 216 patients in the continued methotrexate group, 147 (68%) of 217 patients receiving upadacitinib 15 mg, and 153 (71%) of 215 patients receiving upadacitinib 30 mg (p < 0.0001 for both doses vs continued methotrexate). ^[125]

The SELECT-COMPARE study evaluated safety and effectiveness of upadacitinib compared with adalimumab (each with methotrexate) over 48 weeks. Results showed low disease activity, clinical remission, and improvements in pain and function remained superior for upadacitinib compared with adalimumab at 26 weeks and also from weeks 26 to 48. ^[126]

Combination DMARD therapy

In clinical trials, 30-70% of patients using DMARDs, either as monotherapy or in combination therapy, achieve partial responses, as determined by the ACR disease activity score. Currently, it is not possible to predict which patients will not have a treatment response.

In clinical practice, three strategies are employed to reduce disease activity as much as possible in patients whose disease does not respond or in those with clinical responses that are regarded as insufficient:

• Increasing the dose of medication
• Switching to other DMARDs
• Initiating combination therapy

Because patients may require 2-3 months to achieve a full response to DMARDs, decisions regarding changes in medication are often delayed until that time.

Combination therapy appears to be helpful in patients whose disease partly or completely fails to respond to DMARD monotherapy. One study found that in patients with early, active RA, combination DMARD therapy with downward titration or intensive triple-DMARD combination therapy is more cost-effective than DMARD monotherapy. ^[127] Several combinations have proved successful without posing unexpected added risks; most include MTX (eg, MTX plus SSZ plus HCQ, MTX plus leflunomide, or MTX plus biologic DMARDs).

MTX combined with infliximab ^[128] or rituximab ^[129] yields a better response than monotherapy does. MTX combined with etanercept provides a higher rate of meaningful clinical response. MTX combined with cyclosporine, though not a commonly used combination, results in greater clinical improvement than MTX alone. Triple therapy with MTX, SSZ, and HCQ may provide substantially greater clinical improvement than either MTX alone or SSZ plus HCQ. ^[130]

In new-onset early RA, the use of MTX in combination with biologic DMARDs—mainly, TNF inhibitors—has not shown sufficient superiority to MTX with or without additional conventional synthetic DMARDs to justify first-line use. In the VEDERA (Very Early Versus Delayed Etanercept in Patients With RA) trial, remission rates with etanercept plus MTX versus treat-to-target MTX (with etanercept added in patients not in remission at 24 weeks) were 38% vs 33% at week 24 and 52% vs 38% at week 48, respectively (odds ratios 1.6, 95% CI 0.8-3.5, P=0.211). The study data suggested that delaying etanercept until failure of methotrexate was linked to poorer response to etanercept; that finding requires validation. ^[131]

The VEDERA results failed to confirm the large effect size (30%) suggested in previous exploratory analysis of first-line TNF inhibitor plus MTX compared with treat-to-target MTX. This highlights the fact that even when clinicians incorporate all the recommended treat-to-target strategies in treatment-naïve patients with early RA (ie, symptoms for ≤12 months), a ceiling effect exists. ^[131]

The toxicities of these drug combinations are rarely more significant than those occurring with any of the individual agents used alone, though liver and bone marrow toxicity may be increased if MTX and leflunomide are combined.

Adverse effects

When used with appropriate clinical and laboratory control monitoring, combination therapy with the above agents is usually well tolerated. Adverse events typically become rarer after the first 2-3 months of therapy. Most adverse events are reversible with cessation of the drugs or with reduction of the doses.

The most important and most common adverse events are as follows:

• Liver and bone marrow toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, and D-penicillamine)
• Kidney toxicity (cyclosporine, parenteral gold salts, and D-penicillamine)
• Pneumonitis (MTX)
• Allergic skin reactions (gold compounds and SSZ)
• Autoimmunity (D-penicillamine, SSZ, and minocycline)
• Infections (azathioprine and cyclosporine)

Antimalarial agents may cause ocular toxicity. In addition to an assessment of renal and liver function, it is recommended that baseline ophthalmologic screening for patients using these agents should include an evaluation for visual impairment and a recording of near visual acuity. ^[132] In 2011, the American Academy of Ophthalmology issued Revised Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy.

Complications of DMARD treatment

Patients with an established diagnosis of RA who are being treated with DMARDs, particularly those treated with combination therapy, including biologic agents such as TNF antagonists, may present with serious infections, malignancies, or both. ^{[133, 134, 135]} Additionally, adverse events from RA medications may include liver toxicity, renal toxicity, bone marrow depression, lung inflammation, and skin manifestations.

TNF precautions and mortality

Patients taking anti-TNF agents must avoid live-virus vaccines (eg, measles-mumps-rubella [MMR], HZV, varicella-zoster virus [VZV], and bacillus Calmette-Guérin [BCG] vaccines) to avoid the potential for serious infection.

A large national prospective cohort study over a mean of 4 years demonstrated that anti-TNF therapy for RA was not associated with a significant increase or decrease in mortality when compared with standard nonbiologic DMARD therapy. ^[136] The results from another study confirmed that the risk of serious infection and malignancy is not increased in patients receiving anti-TNF therapy when the patients have early RA and have not been previously treated with MTX or other DMARDs. ^[137]

In a systematic review and meta-analysis reporting on the risk of malignancy in patients with RA treated with TNF inhibitors, the data reviewed showed that these agents did not increase the risk of malignancy, particularly lymphoma; however, they did appear to increase the risk of skin cancer, including melanoma. ^[138]

Corticosteroids

Corticosteroids are potent anti-inflammatory drugs that are commonly used in patients with RA to bridge the time until treatment with DMARDs is effective. ^{[5, 139]} These agents are effective adjuncts to DMARD or NSAID therapy. Timely dose reductions and cessation are important because of the adverse effects associated with long-term steroid use. Corticosteroids can be administered by oral, IV, or intra-articular routes.

When Buttgereit et al studied circadian rhythms in 288 patients with active RA, half of whom were randomly assigned to a modified-release (MR) prednisone tablet and the other half to an immediate-release (IR) prednisone tablet, there was a clinically relevant reduction of morning stiffness of the joints with the MR product as compared with the IR product. ^[140]

A 9-month extension of the same study showed that the MR prednisone taken at bedtime was well tolerated and provided a sustained improvement. ^[141] A third study that added low-dose MR prednisone to existing DMARD treatment also showed improvements in RA signs and symptoms, including a reduction in morning stiffness as compared with baseline (35% vs 55%). ^[142]

A comparison of high-dose IV steroids with infliximab in the 18-month randomized, double-blind IDEA study found similar rates of remission induction and sustained remission, as well as the time to sustained remission, with the two agents. ^[143] The study, which included 112 patients with new-onset DMARD-naïve RA, compared the efficacy of infliximab and IV steroid therapy, both in combination with methotrexate, as remission induction in early RA, followed by a treat-to-target approach.

Adverse effects

One study found that the use of corticosteroids was associated with heart failure in patients with RA, independent of cardiovascular risk factors and coronary heart disease (CHD). Those patients who currently used MTX showed a lower risk of heart failure. ^[144]

Nonsteroidal anti-inflammatory drugs

NSAIDs interfere with prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (COX), thus reducing swelling and pain. However, they do not retard joint destruction and thus are not sufficient to treat RA when used alone. Like corticosteroids, NSAIDs can be reduced in dose or discontinued with successful DMARD therapy.

The several dozen NSAIDs that are available can be classified into several different groups of compounds. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, piroxicam, and diclofenac.

In the early 1990s, a second isoform of COX was discovered (COX-2). COX-1 has a protective role, particularly in the stomach, whereas COX-2 is strongly upregulated during inflammation. Traditional NSAIDs are nonselective COX inhibitors, inhibiting both COX-1 and COX-2. Several coxibs (selective COX-2 inhibitors) were developed that had a significant preference for COX-2 over COX-1. Currently, however, only one COX-2 inhibitor remains on the US market—namely, celecoxib.

Adverse effects

Coxibs, with their selectivity for COX-2, have been shown to be clinically efficacious and produce less gastrointestinal (GI) toxicity, the major adverse event related to the use of nonselective COX inhibitors (ie, NSAIDs). Other adverse effects, such as water retention, hypertension, and abnormal transaminase levels, are observed with both nonselective COX inhibitors and selective COX-2 inhibitors.

Whether and to what degree nonaspirin NSAIDs, coxibs, or both have increased cardiovascular toxicity has not been definitively settled. An analysis of 6 placebo-controlled trials comparing celecoxib with placebo found that the risk of cardiovascular death, myocardial infarction, stroke, heart failure, or thromboembolic events increased after celecoxib treatment in a dose-dependent fashion. ^[145]

Analgesics

Acetaminophen, tramadol, codeine, opiates, and various other analgesic medications can also be used to reduce pain. These agents do not affect swelling or joint destruction.

Experimental therapies

Despite significant advances over the past decades, RA continues to be a chronic disease. It remains active in many patients whose conditions partially or completely fail to respond to DMARDs. Therefore, the vigorous search for new therapeutic agents continues.

Several new CD20 B-cell−targeted biologic agents are under investigation, including atacicept, AMG 623, B3-FCc, Br3-Fc, belimumab, epratuzumab, ofatumumab, ocrelizumab, and TRU-015. Small molecules directed at enzymes involved in signal transduction of TNF and other proinflammatory cytokines are effective in treating RA.

A phase II study reported that in comparison with placebo, fostamatinib, an inhibitor of spleen tyrosine kinase (Syk), reduced disease activity in RA patients who did not have a response to MTX therapy. ^[146] However, a phase III study reported a lower level of response to fostamatinib than the phase II study, with statistically significant but not clinically significant improvements in the ACR20 compared with placebo at 24 weeks and no significant difference in the modified total Sharp/van der Heijde score of radiographic damage. ^[147]

Inhibition of matrix metalloproteinases (MMPs), though initially unsuccessful, could prove to be efficacious, as could inhibition of osteoclast activation. Apheresis procedures are also being investigated. High-dose immunosuppression combined with autologous stem cell transplantation has been used in study protocols for patients whose conditions are resistant to other therapies.

Acute presentations in patients with RA are generally because of an exacerbation of known disease or manifestations in other organ systems or other disease sequelae. Patients presenting with an initial onset of previously undiagnosed possible RA require symptomatic treatment with NSAIDs and rapid referral for definitive diagnosis and institution of DMARD therapy. A delay of as little as 2-3 months in initiating joint-sparing therapy can result in significant irreversible joint damage measured radiographically at 5 years.

In patients with known disease, increased pain, edema, and dysfunction are characteristics of rheumatoid flare (exacerbation). Flares may be local or systemic in nature. Laboratory evaluation may reveal elevation in acute-phase reactants. Treatment consists of rest, NSAIDs, DMARDs, short courses of steroids (2-4 weeks), and, possibly, intra-articular steroid injections. Pain relief is important and may necessitate short-term use of narcotic analgesics.

Felty syndrome

Felty syndrome is a triad of RA, neutropenia, and splenomegaly. Patients with Felty syndrome are prone to serious bacterial infections that result in higher morbidity and mortality than those reported for other patients with RA. Prompt diagnosis and initiation of antibiotic therapy are required.

Baker cysts

Ruptured Baker cysts are often confused with deep vein thrombosis (DVT). Baker cysts often occur fairly early in the course of the disease, with pain, edema, and inflammation in the posterior knee and calf. The diagnosis is best made with ultrasonography. Treatment includes rest, elevation, needle puncture of the calf, knee joint aspiration, and referral.

Carpal tunnel syndrome

Carpal tunnel syndrome (median nerve compression neuropathy) is evinced by pain or paresthesias in the median nerve distribution of the hand, a positive Phalen or positive Tinel test, or positive findings on electromyography (EMG). Therapy includes rest, temporary immobilization, NSAIDs, and surgery.

Pregnancy

Pregnancy alters the immune state, and often—though not always—ameliorates disease activity in women with RA. ^{[148, 149]} No specific guidelines address obstetric monitoring in patients with RA.

Because few available data suggest a significant risk of preterm birth, preeclampsia, or fetal growth restriction in pregnant patients with RA, no special obstetric monitoring is indicated beyond what is performed for usual obstetric care (eg, stabilizing the disease before conception and using drugs safe for pregnancy and lactation). ^[150]

Medications considered low-risk in pregnancy include immunomodulating drugs, low-dose corticosteroids, antimalarial agents, SSZ, and azathioprine. Fetal toxicity is rarely associated with HCQ at the dosage used for RA and connective tissue disease (6.5 mg/kg body weight). ^[151] Anakinra may be used until conception.

Before therapy is initiated, patients should be counseled about the teratogenicity and adverse effects of the medications used to treat RA. NSAIDs should be avoided in the third trimester. MTX is contraindicated in pregnancy, because it is an abortifacient and has teratogenic effects, including craniofacial abnormalities, limb defects, and central nervous system (CNS) defects such as anencephaly, hydrocephaly, and meningomyelopathy, especially with first-trimester exposure. ^[152] Leflunomide is also contraindicated. Both MTX and leflunomide should be discontinued at least 3 months before pregnancy, and blood levels of leflunomide should be assessed.

Use of anti-TNF drugs during pregnancy is not covered by current guidelines. ^{[153, 5, 4]} Stopping TNF inhibitors at conception has been recommended. ^[150] However, TNF inhibitors do not cross the placenta until the end of the second trimester. Thus, concern over possible effects on the development of the fetal immune system has led to the suggestion, in the inflammatory bowel disease literature, that anti-TNF drugs can continue from conception through the first trimester but should be stopped during the second trimester. ^[154]

Analysis of data from the health registries in Denmark and Sweden determined that women who received anti-TNF agents during pregnancy had a slightly higher risk of having children with birth defects. However, the increased risk was not statistically significant. ^[155]

Patients may need a reminder about the importance of using contraception during DMARD therapy and about the necessity of discontinuing some of these medications several months before conception is planned. In addition to discontinuance, some patients who take DMARDs may require treatment with other medications to enhance their clearance.

Patients with RA must be monitored closely after delivery because of the potential for arthritis flareups to occur during the postpartum period.

For complete information on this topic, see Rheumatoid Arthritis and Pregnancy.

Goals of rehabilitation for RA patients include the following:

• Relief of pain
• Improvement in range of motion (ROM)
• Enhancement of strength and endurance
• Prevention or correction of deformities
• Provision of counseling and educational services

Nonpharmacologic therapeutic modalities that are available to the physiatrist to assist patients in achieving these goals include the following ^{[156, 157, 158]} :

• Splints and orthotics
• Assistive equipment
• Joint-protection and energy-conservation techniques
• Education
• Therapeutic exercise programs

Heat and cold therapies

Application of heat, either superficial or deep, is an effective modality for the relief of joint pain and stiffness caused by RA. In addition, it is used to treat joints in preparation for ROM, stretching, and muscle-strengthening exercises. Superficial and deep heating methods have been shown to raise the intra-articular temperature in patients with RA. Heat may be delivered via the following:

• Moist hot packs
• Electric mittens
• A hot shower
• Spas
• Ultrasonography
• Diathermy
• Paraffin

Cold is preferable for treatment of an acutely inflamed joint. Application of cold results in decreased pain and decreased muscle spasm. Cold may be delivered via ice packs, ice sticks, topical sprays, or ice water.

Orthotics and splints

Orthotic devices play an important role in the rehabilitation management of patients with RA. These devices are used to decrease pain and inflammation, improve function, reduce deformity, and correct biomechanical malalignment.

Lower-extremity orthoses are prescribed to provide stability and proper alignment or to shift weight-bearing off the affected limb. The most common orthoses used for the lower extremity involve the foot and ankle joints.

Approximately 80% of patients affected by RA have significant foot involvement. These problems are easily accommodated by providing a deep, wide, soft leather shoe. A metatarsal pad or bar is typically used to remove weight from painful metatarsophalangeal (MTP) joints, and a rocker-bottom sole can be used to facilitate rolloff. Hindfoot pronation should be addressed with custom inserts.

Knee orthoses may be used to control the following problems:

• Edema
• Pain
• Patellar misalignment
• Hyperextension
• Collateral or cruciate ligament instability

Therapeutic exercise

Fatigue and decreased endurance are frequent symptoms in patients with RA. When these patients are compared with age-matched subjects who do not have RA, a reduction in aerobic capacity and muscle strength is noted, both because of the disease itself and because of the lack of physical activity in these patients. Thus, exercise is an important part of rehabilitation management of RA.

Aerobic conditioning in affected patients (if tolerated) improves maximum oxygen uptake and decreases perceived exertion at submaximal workloads, reportedly without causing adverse effects in the joints. In addition, patients undergoing long-term endurance training have been known to feel less isolated, to take less sick leave, and to develop improved function in activities of daily living (ADLs). Patients with well-controlled RA should be encouraged to engage in 30 minutes of daily aerobic exercise several times a week.

A 21-week study by Katz et al in 96 patients with RA found that providing a pedometer and step-monitoring diary, with or without a step target,  increased activity levels and decreased fatigue. A control cohort that received education only showed a trend toward decreased steps. ^[159]

Muscle atrophy often accompanies RA and is exacerbated by inactivity, bed rest, splints, and medications. Isometric exercises restore and maintain strength in affected patients without producing pain. Resistance exercises may be initiated when the isometric program has been well established and when the patient is free of pain. ^[160]

In a review addressing hand function in RA patients, O’Brien suggested that strengthening hand exercises could yield significant improvements in the overall functioning of patients with this disease. ^[161] If surgery is not an option, medical management should be pursued in conjunction with rather thorough physical therapy in order to maintain and preserve hand function. ^[161]

Occupational therapy

Occupational therapy can be very useful for patients with RA. ^[162] Occupational therapy is initiated to help patients achieve the following:

• Using joints and tendons efficiently without stressing these structures

• Decreasing tension on the joints with specially designed splints

• Coping with daily life through adaptations to the patients’ environment and the use of different aids

An occupational therapist may work in conjunction with the physical therapist to ensure that patients are able to meet their goals. The occupational therapist may also assist in the recommendation and use of splints and orthotics, especially when the upper extremity is affected.

Upper-extremity orthoses may be classified as either static or dynamic. Static splints are used to support a weak or unstable joint, to rest a joint for pain relief, or to maintain functional alignment. Dynamic splints traditionally have been used to manage the postoperative hand, but they may also be used to increase manual dexterity. The most commonly used splints for the hand are the finger-ring splint and the thumb-post splint. The functional wrist splint and the resting hand splint are commonly used for wrist splinting.

Adaptive equipment

Many assistive devices are available to patients with RA and are used to maximize function, maintain independence, reduce joint stress, conserve energy, and provide pain relief. Equipment is available to assist patients with transfers, dressing, feeding, toileting, cooking, and ambulation. Physical and occupational therapists can assist with training in the use of adaptive equipment.

Joint-protection education

Joint-protection education provides the patient with techniques and recommendations for preventing joint overuse and avoiding of biomechanical torques that excessively bend the joint. ^[156] The use of adaptive equipment is important. Other components of a good joint-protection program include the following:

• Maintenance of good posture
• Avoidance of overuse during inflammation
• Modification of tasks to decrease joint stress
• Use of appropriate splints

Energy-conservation education

Fatigue is a major component of RA, and it is due to the systemic nature of the disease, as well as to the decreased cardiovascular endurance observed in patients with this inflammatory disorder.

The goal of energy conservation techniques is to save energy while maximizing function. Adaptive equipment is an essential part of this program. Other elements include maintaining joint ROM and strength, improving cardiovascular fitness, and taking short rest periods during the day. Every individual with RA should implement joint-protection and energy-conservation programs into his or her lifestyle.

Williams et al found that in older women with either RA or osteoarthritis of the lower limb, an individualized home program of balance-training exercise can improve balance and gait stability. ^[163] In this study, 39 women (mean age, 69.3 years) underwent a 4-month program of balance exercises conducted by a physical therapist. Before exercise training, 64% of patients reported having had fallen during the previous 12 months, and 42% of patients had a moderate fall-risk score.

After the 4-month program, the patients demonstrated improvement on most balance measurements, including their fall-risk score and measurements of activity level, fear of falling, functional reach, and step width. ^[163] Improvements were also seen in patients’ body mass index (BMI) and in their sit-to-stand rising index.

Surgical intervention in patients with RA can relieve pain, correct deformity, and improve function. ^[156] A number of surgical procedures are available to obtain these goals, such as myofascial techniques, excisions, reconstructions, joint fusions, and joint replacements. The timing of surgery is a complex decision; the patient’s age, stage of disease, and level of disability, as well as the location of the involved joints, must be considered. Early surgical intervention may help maintain a patient’s functional level of independence.

Deformities of the hand or wrist lead to loss of the ability to grip, grasp, and pinch, often leaving the patient unable to perform the activities of daily living. The surgical treatments for RA of the hand and wrist include the following:

• Synovectomy
• Tenosynovectomy
• Tendon realignment
• Reconstructive surgery or arthroplasty
• Arthrodesis

Cervical spine instability may develop in patients with established RA who have degeneration of the ligaments and bone in the C-spine area. Degeneration of the transverse ligament can lead to instability at the C1-C2 level. Minor trauma can lead to neurologic sequelae due to inherent instability.

Exercise caution in evaluating RA patients after minor falls, motor vehicle accidents, or other injuries. Cervical spine injury may occur spontaneously. Patients with long-standing disease may need careful evaluation perioperatively to detect any cervical spine instability before neck manipulation or intubation during surgery. Patients with RA of the cervical spine who have refractory pain, clearly evident neurologic compromise, or intrinsic spinal cord signal changes on magnetic resonance imaging (MRI) are generally candidates for surgical intervention.

For more information on these topics, see Hand and Wrist Surgery in Rheumatoid Arthritis and Rheumatoid Arthritis of the Cervical Spine.

Studies in Muslim patients have reported improvement in RA disease activity associated with the intermittent fasting practiced during Ramadan (ie, from sunrise to sunset for a month). ^{[164, 165, 166]} Ben Nessib et al compared Disease Activity Scores (DAS) 28 assessed 6 months before starting Ramadan fasting and the second after at least 7 days of fasting in 36 patients with RA, and recorded a decrease from 4.3 to 3.5 (P <  0.001). ^[165] A subsequent study by this group in 35 patients demonstrated that the positive effects of fasting can persist for as long as 3 months. ^[166]