that all patients be screened for latent tuberculosis infection (LTBI) prior to initiation
of a bDMARD or tofacitinib. If LTBI is identified, patients should receive at least 1
month of treatment prior to starting a bDMARD or tofacitinib. Patients with active
TB should complete treatment prior to initiation of a bDMARD or tofacitinib.
Patients should be monitored for active TB during treatment.
It is recommended that patients receive the following vaccinations prior to the
initiation of csDMARD or bDMARD therapy: pneumococcal, influenza, hepatitis B,
human papillomavirus, and herpes zoster. However, if not completed prior to the
initiation of therapy, these vaccinations, with the exception of herpes zoster, may be
given following the initiation of csDMARDs or bDMARDs. Herpes zoster, as well
as any other live vaccines, should not be administered in patients receiving
Corticosteroids (i.e., low oral doses for multiple joint involvement or injections into
isolated joints) can be used as needed at disease onset while awaiting response to
DMARD therapy and intermittently during disease flare-ups or following failure of
optimized treatment to control symptoms of pain and swelling. Corticosteroids have a
long history of use in RA because of their potent anti-inflammatory and
immunosuppressive effects and have been shown to enhance the clinical, functional,
and structural efficacy of baseline csDMARD or combination csDMARD and
26 Corticosteroids administered orally at low dosages or through
local injections are effective in rapidly reducing disease activity and relieving RA
Corticosteroids are particularly beneficial when patients are awaiting the onset of
DMARD action (known as “bridge therapy”) or during flares of active RA involving
28,61 Oral corticosteroids seem to slow the rate of disease
progression and have been shown to reduce radiographic changes for 1 to 2
36,61,62 Use of corticosteroids in combination with DMARD therapy appears to
improve clinical outcomes (signs and symptoms, functionality, radiologic damage)
for patients with RA above the benefit of a DMARD used alone.
newer modified-release corticosteroids targeting nocturnal increases in inflammatory
mediators, IL-6 and cortisol, have demonstrated a reduction in morning stiffness
compared with older, standard immediate release agents.
corticosteroids, however, is associated with many serious adverse effects (e.g.,
osteoporosis, weight gain, diabetes, cataract formation, adrenal suppression,
hypertension, infections, and impaired wound healing).
corticosteroid dosing should be limited to daily doses of ≤10 mg of prednisone (or
equivalent) and should be administered for as short a time as possible.
corticosteroid injections for an extended period have the potential to accelerate bone
and cartilage deterioration; therefore, the same joint should not be injected more than
SELDOM-USED DISEASE MODIFYING ANTIRHEUMATIC DRUGS AND
Several DMARDs, including gold, azathioprine, cyclosporine, minocycline, and
anakinra, are no longer included in EULAR and ACR treatment recommendations
because of infrequent use and lack of any new data supporting clinical benefit,
in light of other widely available agents with more favorable benefit-to-risk
nitric oxide donors, are standard NSAIDs structurally linked to a nitric oxide moiety.
By donating nitric oxide to the gastric mucosa, nitric oxide NSAIDs produce the
same gastroprotective effect as prostaglandins and have a lower rate of
gastrointestinal ulceration compared to classic agents.
dual-inhibitor NSAIDs, blocks both enzymatic pathways of arachidonic acid
metabolism (i.e., both COX and 5-lipoxygenase) and further broadens the
pharmacologic effects of currently available NSAIDs. Although COX inhibition is
clearly associated with GI toxicity, inhibition of both enzymatic pathways of
arachidonic acid metabolism has been GI sparing in animal and initial human safety
RA vaccines are also in development.
70 Only phase II studies have been
completed, but a recent trial demonstrated clinical improvement in the majority of
RA patients receiving T cell immunotherapy.
71 This RA vaccine induces a specific
immune response against T cells that are reactive to joint antigens.
using immune-modulatory therapy targeted toward anti-CCP autoantibodies also
demonstrated clinical improvement in patients with active RA.
CLINICAL USE OF DISEASE-MODIFYING ANTIRHEUMATIC DRUGS
27 have developed evidence-based
recommendations for the use of DMARDs in RA, last updated in 2015 and 2013,
respectively. The two sets of guidelines have more similarities than differences.
Ultimately, choice of treatment modality will be based on efficacy and safety data as
well as on patient-specific parameters.
DMARD treatment should be started as soon as possible following RA diagnosis.
MTX remains the gold standard because of high response rate, mild side effect
profile, low cost, and long sustained efficacy not just as monotherapy but also in
combination with glucocorticoids, other csDMARDs, and bDMARDs.
Furthermore, MTX therapy is associated with a reduction in cardiovascular
morbidity and mortality in patients with RA, important given the strong association
between RA and cardiovascular disease.
25 Optimization of MTX therapy also
involves appropriate dose titration, adequate trial duration, and folate
supplementation. Regardless of disease duration, ACR recommends that in the setting
of low, moderate, or high disease activity, a trial of MTX as monotherapy may be
started initially, with success predicted in 25% to 50% of individuals within 1
In the setting of moderate or high disease activity unresponsive to csDMARD
monotherapy, EULAR recommends use of csDMARD combination therapy.
csDMARD combination therapy with MTX may also be considered in the setting of
moderate or high disease activity with poor prognostic features (i.e., functional
limitation, extra-articular disease, positive RF or anti-CCP, and bony erosions). The
most common combination is MTX, SSZ, and HCQ, which has been shown to attain
treatment goals faster and with less therapy intensification than MTX monotherapy.
Culmination of current data suggests that combination csDMARD therapy may be
superior to MTX monotherapy, but results remain controversial because of
limitations of the studies themselves. Ultimately, MTX as monotherapy or in
combination with other csDMARDs are both appropriate as first-line therapy and
selection is determined by patient-specific factors.
contraindication or intolerance, LEF or SSZ, alone or in combination, may be
considered as first-line csDMARDs instead. Both agents have demonstrated similar
In addition to combination csDMARD therapy, ACR
also considers addition of a bDMARD (either TNF inhibitor or non-TNF bDMARD)
as a viable treatment strategy in the setting of csDMARD monotherapy failure in
either early (disease duration <6 months) or established (disease duration ≥6 months)
RA. The addition of tofacitinib may also be considered for patients with established
RA and moderate-to-high disease activity.
If desired response is not achieved with optimized dosing of the first-line
treatment approach within the desired time frame, step-up therapy is warranted. If
poor prognostic factors are not present, EULAR recommends the patient trial another
csDMARD(s) (i.e., LEF, SSZ, and/or MTX as mono- or combination therapy). If
prognosis is poor, then addition of a bDMARD to current csDMARD therapy is
warranted. Ultimately, for patients on csDMARD therapy who remain unresponsive,
bDMARDs should be initiated as add-on therapy to the csDMARD.
For choice of initial bDMARD, EULAR recommends TNF inhibitors, abatacept or
tocilizumab, and in certain clinical scenarios, rituximab, as add-on therapy.
TNF inhibitors have a larger evidence base and extended history of use compared to
the non-TNF agents, more recent trial data have not triggered safety concerns for the
76–79 Rituximab may be considered as a first-line bDMARD in patients
having certain contraindications to other bDMARDs such as recent lymphoma, since
this agent is not associated with malignancy.
80–82 ACR gives no preference to any
bDMARD over another. Anakinra, the IL-1 inhibitor, is not included in either ACR
or EULAR recommendations given lack of efficacy when compared to other
bDMARDs and its minimal use in clinical practice.
Triple csDMARD therapy has been shown to be non-inferior to combination MTX
and TNF inhibitor therapy. There is a lack of trial data comparing csDMARDs to
It is preferred that the bDMARDs be used in
combination with either MTX or other csDMARDs rather than as monotherapy.
Furthermore, even if clinical response is achieved with combination therapy, the
csDMARD(s) should not be discontinued. If a patient truly cannot be treated with
csDMARDs, consideration may be given to monotherapy with etanercept,
adalimumab, certolizumab pegol, abatacept or tocilizumab.
If a patient has an inadequate response to the initial bDMARD trial, another
bDMARD trial is warranted. There is no preferred step-up bDMARD and choice is
dependent on patient-specific factors. However, if a TNF inhibitor was initially
switching to another non-TNF bDMARD is preferred. Finally, while indicated for
individuals with moderate-to-severe RA who have failed MTX therapy, given the
lack of clinical experience and safety data compared to bDMARDs, tofacitinib may
be considered following multiple bDMARD treatment failures (i.e., at least one TNF
inhibitor and two non-TNF bDMARDs).
QUANTIFYING RESPONSE TO DRUG THERAPY
RA disease remission is the highest aim of therapy and has become more realistic as
medications capable of halting or slowing disease progression are now widely
available and commonly used in clinical practice. The ACR and EULAR consider
patients with RA in clinical trials to have achieved remission if either of the
all less than 1 or (2) Simplified Disease Activity Index is less than 3.3.37 (Table 44-
3). The proportion of patients able to achieve remission with this validated clinical
assessment tool is adequate enough to encourage adoption of these criteria in
standard practice. If disease remission is unattainable, then minimizing disease
activity to provide pain relief, maintain activities of daily living, maximize quality of
life, and slow joint damage become primary targets.
Figure 44-6 2015 American College of Rheumatology recommendations for the treatment of established
treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):12.)
Provisional Criteria for Rheumatoid Arthritis Remission in Clinical Trials from
the American College of Rheumatology/European League Against Rheumatism
At any time, patient must satisfy ALL of the following:
Patient global assessment ≤1 (on a 0–10 scale)
At any time, patient must have a Simplified Disease Activity Index score of ≤3.3
and ankles, and it is preferable to include feet and ankles also when evaluating remission.
the patient’s current disease activity?” (anchors: none–extremely active).
In active disease, successful implementation of the treat to target approach
requires reevaluation of pharmacologic therapy every 1 to 3 months. Therapy
adjustment no later than 3 months into the treatment course is warranted because if
there is no improvement by this time then it is unlikely that continuing the same
course will achieve satisfactory results. Once treatment targets have been achieved,
monitoring may occur less frequently every 6 to 12 months. In patients with good
response, glucocorticoids should be the first medications tapered and withdrawn, and
if remission is sustained then tapering and discontinuing DMARD therapy (all types)
28 This is a conditional ACR recommendation; while the quality
of evidence supporting this recommendation is low in terms of the risk of disease
exacerbation/recurrence, the long-term risk and cost of continuing therapy that is
potentially unnecessary makes this a valid consideration.
Evaluating treatment response using validated clinical assessment tools yield a
more accurate assessment of disease activity and improve the likelihood of attaining
disease remission through modifications of drug therapy.
response criteria; however, these are designed for clinical research and may not be
practical for clinical practice.
89 Although there is no single tool adopted as the
standard of practice in the clinical setting, there are various other validated
assessment tools that are advantageous for objectively evaluating disease activity and
tracking disease progression (Table 44-4). These tools use various combinations of
28-tender joint count, acute phase reactant measures, pain and function assessments,
and patient and physician global assessments of disease activity to determine disease
activity. For example, The Clinical Disease Activity Index (CDAI) and the
Simplified Disease Activity Index (SDAI) scores are determined through a simple
sum of swollen joint count, tender joint count, patient global disease activity, and
evaluator global disease activity (both measured by a visual analog scale). However,
the SDAI includes CRP in the summation, whereas the CDAI does not.
important to note that all of these tools have distinctly defined threshold scores
corresponding to high disease activity, low-to-moderate disease activity, low
disease activity, and remission, although there is little agreement among the tools in
terms of classifying a patient’s RA activity level. Choice of tool is typically practicespecific.
The scoring tools listed above should be used in conjunction with radiographic
evaluation to determine RA course and treatment strategy. Conventional radiography
was previously considered the gold standard, but imaging via computed tomography,
ultrasound, and magnetic resonance imaging is now available and may offer some
benefit in improved resolution compared with standard radiograph technology.
Radiographic changes occur in more than half of patients categorized in remission
and tracking these can help clinicians objectively evaluate arthritis-related joint
Tools Used to Measure Disease Activity in Rheumatoid Arthritis
Thresholds of Disease Activity
Disease Activity Score in 28 joints 0–9.4 ≤3.2 >3.2 and ≤5.1 >5.1
Simplified Disease Activity Index 0.1–86.0 ≤11 >11 and ≤26 >26
Clinical Disease Activity Index 0–76.0 ≤10 >10 and ≤22 >22
Rheumatoid Arthritis Disease Activity
Patient Activity Scale (PAS) or PASII 0–10 ≤1.9 >1.9 and ≤5.3 >5.3
Routine Assessment Patient Index Data 0–30 ≤6 >6 and ≤12 >12
rate, and measures of general health or global disease activity.
NONSTEROIDAL ANTI-INFLAMMATORY DRUG THERAPY
CASE 44-1, QUESTION 4: T.W. will be treated with a DMARD and concurrent NSAID therapy initially to
T.W.’s clinical presentation clearly warrants DMARD therapy (see Case 44-5,
Question 4, and Clinical Use of Disease-Modifying Agents section). The purpose of
NSAID therapy, which has no disease-modifying activity, is to provide rapid pain
relief and reduction of joint inflammation primarily as bridge therapy while awaiting
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