1. A NEW LOOK AT RA Interactive Hot Topics Series
Implementing Treat to Target:
A Case Study in RA
I’m going to spend the next 15 minutes discussing treating to target in patients with RA. In this discussion, we will follow a newly diagnosed patient with RA over his first 6 months of evaluation and treatment aimed at achieving remission of disease.
MP-RA-0267

2. The Treat-to-Target Paradigm
Adapt therapy according to disease activity*
(consider comorbidities and other patient factors)
Adapt therapy if state is lost*
(consider comorbidities and other patient factors)
Main target
Active RA
Remission
Sustained remission
Use a composite measure of disease activity every 1 ‒ 3 months
Assess disease activity about every 3 ‒ 6 months
Before we begin to review the case, it is useful to consider the treat-to-target paradigm originally published by Josef Smolen and colleagues and most recently updated in Simply stated, this approach emphasizes iterative patient assessment and adjustment of treatment to achieve sustained remission or the alternative treatment goal of sustained low disease activity.
Low disease activity
Sustained low disease activity
Adapt therapy according to disease activity*
(consider comorbidities and other patient factors)
Adapt therapy if state is lost*
(consider comorbidities and other patient factors)
Alternative target
*Shared decision with patient
RA, rheumatoid arthritis
Reproduced from Smolen JS, et al. Ann Rheum Dis. 2016;75:3-15. © 2016, with permission from BMJ Publishing Group.

3. Key Principles in Treating to Target
The primary target for treatment of RA should be a state of clinical remission
Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity
While remission should be a clear target, based on available evidence, low disease activity (LDA) may be an acceptable alternative therapeutic goal, particularly in established, long-standing disease
Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 to 6 months
Measures of disease activity must be obtained and documented regularly, as frequently as monthly for patients with high/moderate disease activity, or less frequently (such as every 3 to 6 months) for patients in sustained low disease activity or remission
The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions
Structural changes and functional impairment should be considered when making clinical decisions, in addition to assessing composite measures of disease activity
The desired treatment target should be maintained throughout the remaining course of the disease
The choice of the (composite) measure of disease activity and the level of the target value may be influenced by considerations of comorbidities, patient factors, and drug-related risks
The patient has to be appropriately informed about the treatment target and the strategy planned to reach this target under the supervision of the rheumatologist
This slide enumerates the key principles of the treat-to-target approach for management of patients with RA. The most important points are highlighted in red and they include the principles that the primary target for treatment of RA should be a state of clinical remission; drug therapy should be adjusted at least every 3 to 6 months until the treatment goal is reached; and that the use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions.
Treat to Target Available at:

4. Treating to Target in Practice: Case Study*
Bob is a 45-year-old carpenter
He presents with a 5-month history of joint pain in his hands, feet and knees and he also has morning stiffness with a duration of 3-4 hours
This is our patient, Bob. He is a 45-year-old carpenter who presents with a 5-month history of joint pain in his hands, feet and knees. He also has morning stiffness with a duration of 3-4 hours that interferes with his ability to work.
* Hypothetical case; not based on actual patient

5. Case Study: Assessment of Disease Activity
Physical examination:
15 tender joints
13 swollen joints
PtGA: 7.5/10
EGA: 7.1/10
Imaging:
No erosions or joint space narrowing
Laboratory values:
ESR: 36 mm
CRP: 4.2 mg/dL
RF: negative
Anti-CCP: 24 U
Physical examination and laboratory evaluation indicate significant disease activity. Bob has high numbers of tender and swollen joints and elevated C-reactive protein and ESR. Evaluation of radiographs indicates no erosions or joint space narrowing. He also rheumatoid factor negative and his anti-CCP titer is 24 U.
Anti-CCP, anti-cyclic citrullinated protein antibody; CRP, C-reactive protein; EGA, Evaluator’s Global Assessment; ESR, erythrocyte sedimentation rate; PtGA, Patient’s Global Assessment; RF, rheumatoid factor

6. The CDAI for this patient = 42.6 (high disease activity)1,2
Case Study Question: What Composite Measure Would Be Suitable for Assessment of Disease Severity in This Patient?
DAS-28?
SDAI?
CDAI?
RAPID3?
HAQ?
Other?
As noted a moment ago, treating to target should include use of an objective measure for assessment of disease activity. Calculation of the CDAI score for this patient results in a value of 42.6 and the DAS-28 ESR is Both of these scores are also indicative of high disease activity.
The CDAI for this patient = 42.6 (high disease activity)1,2
CDAI, Clinical Disease Activity Index; DAS-28, Disease Activity Scorse-28 joint; HAQ, Health Assessment Questionnaire; RAPID3, Routine Assessment of Patient Index Data 3); SDAI, Simplified Disease Activity Index
Aletaha D, Smolen J Clin Exp Rheumatol. 2005;23(5 Suppl 39):S
Amercian College of Rheumatology Available at:

7. Case Study: Initiation of Treatment
The treatment goal for this patient is disease remission as reflected by an CDAI score ≤2.8
Treatment for Bob is initiated with:
15 mg/week oral MTX
1 mg/day folic acid (except on the day of MTX administration)
10 mg/day prednisone with a plan to taper and discontinue by 3 months
Bob will be re-evaluated in 6 weeks
The treatment goal for Bob is disease remission and initial treatment is 15 mg/week methotrexate with folic acid; and prednisone to provide rapid symptom relief during the time needed for methotrexate to exert its clinical benefit.
MTX, methotrexate; CDAI, Clinical Disease Activity Index

8. ACR Guidelines Support MTX As Initial Treatment for Early RA
* Consider adding low-dose glucocorticoids (≤10 mg/day of prednisone or equivalent) in patients with moderate or high RA disease activity when starting disease-modifying antirheumatic drugs (DMARDs) and in patients with DMARD failure or biologic failure
† Also consider using short-term glucocorticoids (defined as <3 months treatment) for RA disease flares. Glucocorticoids should be used at the lowest possible dose and for the shortest possible duration to provide the best benefit-risk ratio for the patient
# Treatment target should ideally be low disease activity or remission
Initial treatment with methotrexate is consistent with guidance from the American College of Rheumatology and Bob has no contraindications to the drug. Contraindications to methotrexate include, pregnancy or nursing, alcoholism or liver disease, immunodeficiency syndromes, pre-existing blood dyscrasias, and hypersensitivity to methotrexate.
Singh JA, et al. Arthritis Care Res. 2016;68:1-25. © 2015, American College of Rheumatology.

9. Case Study: 6-week Follow-up
Physical examination:
5 tender joints
3 swollen joints
PtGA: 3.1/10
EGA: 2.7/10
Imaging:
No erosions or joint space narrowing
Laboratory values:
ESR: 22 mm
CRP: 2.6 mg/dL
RF: negative
Anti-CCP: 23 U
The CDAI for this patient = 13.8 (moderate disease activity and a moderate response to treatment)1
After 3 months of methotrexate monotherapy, there has been substantial improvement in Bob’s condition. Tender and swollen joint counts have declined and qualitative assessments have also improved. There have also been reductions in both CRP and ESR. His CDAI and DAS-28 ESR scores are 13.8 and 3.93, respectively. Both of these values are indicative of moderate disease activity.
Anti-CCP, anti-cyclic citrullinated protein antibody; CRP, C-reactive protein; EGA, Evaluator’s Global Assessment; ESR, erythrocyte sedimentation rate; PtGA, Patient’s Global Assessment; RF, rheumatoid factor
1. Smolen JS, Aletaha D. Clin Exp Rheumatol. 2014;32 (Suppl 85):S75-S79.

10. Case Study: Question
What changes in treatment might be appropriate for Bob?
Increase the oral MTX dose?
Add a second synthetic DMARD?
Switch to subcutaneously delivered MTX?
Switch to a biologic agent?
While Bob’s condition has certainly improved, he has not achieved his treatment goal. Thus, augmentation of therapy should be considered. Options for this patient include increasing the oral methotrexate dose; adding a second synthetic DMARD, such as hydrochloroquine or sulfasalazine, to treatment; switching from oral to subcutaneously delivery of methotrexate; or adding a biologic agent to the treatment regimen.
DMARD, disease-modifying antirheumatic drug; MTX, methotrexate

11. Case Study: Augmentation of Treatment
Treatment for Bob is changed to:
20 mg/week oral MTX
1 mg/day folic acid (except on the day of MTX administration)
5 mg/day prednisone with a plan to discontinue at the next visit
Bob will be re-evaluated at 3 months after treatment initiation
Since Bob has had a good response methotrexate the dose is increased and no other agents are added. The prednisone dose is decreased to 5 mg/day and the patient will be evaluated again at 3 months.
MTX, methotrexate

12. Higher MTX Doses Are Associated with Better Clinical Efficacy
Systematic review of the literature on optimal dosage of MTX in patients with RA
Starting doses of 25 mg/week or fast escalation with 5 mg/month to mg/week were associated with higher clinical effect sizes in comparison with doses of mg/week or slow escalation
2.5
2.0
1.5
1.0
0.5
-0.5
-1.0
Effect size
SJC
TJC
Pain
Global
12.5–20 mg/week
5–10 mg/week
Placebo
The decision to increase the dose of methotrexate in this patient is consistent with results from a systematic literature review which suggested that starting on methotrexate 15 mg/week orally, escalating with 5 mg/month to mg/week, or the highest tolerable dose, with a subsequent switch to subcutaneous administration in the case of an insufficient response, is the “optimal evidence-based dosing and routing recommendation for methotrexate in RA”.
RA, rheumatoid arthritis; SJC, swollen joint count; TJC, tender joint count
Reproduced from Visser K, van der Heijde D. Ann Rheum Dis. 2009;68: © 2009 with permission from BMJ Publishing Group.

13. Case Study: 3-month Follow-up
Physical examination:
3 tender joints
3 swollen joints
PtGA: 2.6/10
EGA: 2.3/10
Bob also complains of nausea and mild abdominal pain
Imaging:
No evidence of structural lesions
Laboratory values:
ESR: 20 mm/hr
CRP: 2.3 mg/dL
RF: negative
Anti-CCP: 24 U
At 3 months after the initiation treatment, Bob continues to have moderate disease activity and their has been only a slight change in the CDAI score from the previous visit. The CDAI and DAS-28 ESR and scores at this visit are 10.9 and 3.58, respectively; both are indicative of moderate disease activity.
The CDAI for this patient = 10.9 (moderate disease activity)1
Anti-CCP, anti-cyclic citrullinated protein antibody; CRP, C-reactive protein; EGA, Evaluator’s Global Assessment; ESR, erythrocyte sedimentation rate; PtGA, Patient’s Global Assessment; RF, rheumatoid factor
1. Smolen JS, Aletaha D. Clin Exp Rheumatol. 2014;32 (Suppl 85):S75-S79.

14. Case Study: Question
What changes in treatment might be appropriate for Bob?
Increase the oral MTX dose?
Add a second synthetic DMARD?
Switch to subcutaneously delivered MTX?
Switch to a biologic agent?
Since the patient has not achieved his treatment goal, a change in therapy is indicated. The options at this point include all of those mentioned previously.
DMARD, disease-modifying antirheumatic drug; MTX, methotrexate

15. Case Study: Augmentation of Treatment
Treatment for Bob is changed to:
25 mg/week MTX delivered by subcutaneous injection
1 mg/day folic acid (except on the day of MTX administration)
Prednisone is discontinued
Bob will be re-evaluated in 3 months
While addition of a biologic to treatment is considered and would certainly be appropriate, treatment for Bob is altered by switching from oral to subcutaneous methotrexate administration and increasing the dose to 25 mg. This change is based on pharmacokinetic results showing higher and more consistent bioavailability with subcutaneous methotrexate administration. This also supports increasing the dose and changing the route of administration in an effort to improve the clinical response.
MTX, methotrexate

16. SC Administration Improves MTX Bioavailability
Single center, open label, randomized, 2-period, 2-sequence, single-dose crossover study in 4 dose groups (7.5 mg, 15 mg, mg, and 30 mg) with 54 healthy adults
The results shown on this slide illustrate the increased bioavailability of subcutaneously versus orally administered methotrexate.
In this single-dose, crossover study, healthy subjects aged 18 to 55 years were divided into one of four dose groups: 7.5 mg, 15 mg, 22.5 mg, or 30 mg of methotrexate and each subject received a single dose administered orally and subcutaneously.
Study results indicated higher bioavailability, as reflected by area under the time versus plasma concentration curve, with subcutaneous administration. The difference between the two routes of administration increased with higher methotrexate doses.
MTX, methotrexate; SC, subcutaneous
Pichlmeier U, Heuer KU. Clin Exp Rheumatol ;32:

17. Improved GI Tolerability with SC vs Oral MTX
N=37
VAS Score (0-100)
P=0.053
Concern about adverse events with this change in treatment is reduced by the observation that subcutaneous administration of methotrexate is associated with lower frequency and severity of nausea and lower frequency of abdominal discomfort versus oral administration.
MTX, methotrexate; SC, subcutaneous; VAS, visual analog scale
Adapted from Kromann CB, et al. J Dermatolog Treat. 2014;17:1-3.

18. Significant Improvement of Disease Control Following Switch From Oral to SC MTX
Retrospective analysis of 103 RA patients switched from oral to SC MTX:
40 switched due to inadequate efficacy of oral MTX
63 patients switched due to GI side effects of oral MTX
P=0.006
The potential for clinical benefit with a switch from oral to subcutaneous methotrexate is supported by a retrospective analysis of 103 patients with RA who were switched from oral to subcutaneous methotrexate at a mean dose 15 mg/week a single center in the UK.
Disease control was assessed before and 3 months after switching and patients were divided in to two groups based on reason for switching, inadequate efficacy or intolerance of oral drug.
As can be seen in the figure, there were significant improvements in DAS-28 scores after switching from oral to subcutaneous methotrexate delivery in both groups of patients.
P=0.0001
MTX, methotrexate; SC, subcutaneous; DAS, disease activity score
Hameed B, Jones H. Int J Rheum Dis. 2010;13:e83-e84. © 2010 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd.

19. Case Study: 6-month Follow-up
Physical examination:
1 tender joints
0 swollen joints
PtGA: 0.5/10
EGA: 0.7/10
Nausea and mild abdominal pain have resolved
Imaging:
No erosions or joint space narrowing
Laboratory values:
ESR: 20 mm/hr
CRP: 1.6 mg/dL
RF: negative
Anti-CCP: 24 U
Bob is seen again after 6 months of treatment and his CDAI score has declined to 2.2 which reflects remission. His DAS-28 ESR score is 2.66 and this is also indicative of remission.
The CDAI for this patient = 2.2 (low disease activity approaching remission)1
Anti-CCP, anti-cyclic citrullinated protein antibody; CRP, C-reactive protein; EGA, Evaluator’s Global Assessment; ESR, erythrocyte sedimentation rate; PtGA, Patient’s Global Assessment; RF, rheumatoid factor
1. Smolen JS, Aletaha D. Clin Exp Rheumatol. 2014;32 (Suppl 85):S75-S79.

20. Case Study: Treatment Treatment for Bob:
25 mg/week MTX delivered by subcutaneous injection will be continued
1 mg/day folic acid (except on the day of MTX administration)
Bob will be re-evaluated in 3 months:
If remission is sustained, current treatment will be continued. If not, a further augmentation of therapy will be considered
The patient is continued on 25 mg/week methotrexate delivered subcutaneously and will be re-evaluated in 3 months. If remission is sustained, current treatment will be continued. If not, a further augmentation of therapy with either addition of a biologic or triple therapy with synthetic DMARDs, will be considered.
MTX, methotrexate; SDAI, Simplified Disease Activity Index

21. Summary: Multiple Steps in Treatment May Be Needed to Achieve Goals
Initiate Treatment with Oral MTX/Dose Titration
Inadequate Response/ Intolerance
Switch to SC MTX
Clinical Remission or LDA/Limited Radiographic Progression
The management of this patient illustrates the treat-to-target approach that combines evaluation with a validated composite measure and augmentation of treatment as needed to achieve the treatment goal. It also makes the point that multiple increases in treatment intensity may be required to achieve the treatment goal.
The case also illustrates the potential benefit of switching from oral to subcutaneous delivery of methotrexate to improve exposure to the drug and increase clinical efficacy in patients who have an inadequate response to oral methotrexate or cannot tolerate oral methotrexate.
One Approach to Treating to Target
SC, subcutaneous; LDA, low disease activity
Adapted from Yazici Y, Bata Y. Bulletin of the Hospital for Joint Diseases. 2013;71(Suppl 1):S46-48; Bykerk VP, et al. J Rheumatol. 2012;39: ; Alsaeedi S, Keystone EC. Nat Rev Rheumatol. Advance online publication 5 August 2014.