Differences in treat-to-target in patients with rheumatoid arthritis versus hypertension and diabetes: consequences for clinical care.
Abstract: "Treat-to-target" of rheumatoid arthritis (RA) is similar in many respects to hypertension and diabetes. All three diseases involve a dysregulation of normal physiologic functions, which results in long-term organ damage if not treated. "Treat-to-target" strategies, based on values of specific quantitative measures, lead to improved outcomes, including longer survival. However, RA differs from hypertension and diabetes in at least five important respects: 1. the absence of a single "gold standard" measure in RA for all individual patients necessitates indices; 2. the rarity of acute emergency situations in RA leads to underestimation of its natural history, which includes increased mortality rates similar to hypertension and diabetes; 3. the patient with hypertension or diabetes goes to the doctor to learn how she or he is doing, based on a "gold standard" quantitative measure, while the patient with RA goes to the doctor to tell the doctor how she or he is doing; 4. the history and physical examination in hypertension or diabetes may be recorded as narrative, nonquantitative information, as a vital sign or laboratory test provides the crucial information for clinical care but should be recorded as quantitative, standardized "scientific" data on patient questionnaires and formal joint counts because of their importance in RA; and 5. patient mood or distress may impact directly RA indices used as quantitative measures in a "treat-to-target" strategy, which is not seen in hypertension or diabetes. These matters may be addressed through three global scales completed by health professionals concerning inflammation, damage, or neither inflammation nor damage as a basis for symptoms.
Subject: Diabetes therapy (Health aspects)
Antirheumatic agents (Health aspects)
Arthritis (Care and treatment)
Arthritis (Health aspects)
Medical personnel (Health aspects)
Rheumatoid arthritis (Care and treatment)
Rheumatoid arthritis (Health aspects)
Diabetes (Care and treatment)
Diabetes (Health aspects)
Hypertension (Care and treatment)
Hypertension (Health aspects)
Rheumatoid factor (Health aspects)
Mortality
Authors: Castrejon, Isabel
Pincus, Theodore
Pub Date: 04/01/2011
Publication: Name: Bulletin of the NYU Hospital for Joint Diseases Publisher: J. Michael Ryan Publishing Co. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2011 J. Michael Ryan Publishing Co. ISSN: 1936-9719
Issue: Date: April, 2011 Source Volume: 69 Source Issue: 2
Product: Product Code: 8000431 Diabetes Therapy; 8010000 Medical Personnel NAICS Code: 621 Ambulatory Health Care Services; 62 Health Care and Social Assistance
Accession Number: 289120432
Full Text: "Treat-to-target" with tight control of rheumatoid I arthritis (RA) results in better patient outcomes A compared to traditional approaches. (1-9) "Treat-to-target" in RA is similar in many respects to hypertension and diabetes (Table 1). (10) All three diseases involve a dysregulation of normal physiologic functions. Persistent dysregulation over time results in long-term organ damage, generally correlated with clinical severity, affecting the musculoskeletal, cardiovascular, renal and/or other systems.

The etiology of the dysregulation in all three diseases remains unknown, so no cure is available (Table 1). Nonetheless, medications now are available to control the dysregulation, thereby slowing or even preventing its primary consequence of organ damage. Optimal prevention of organ damage requires "tight control," beyond simple improvement and guided by a "treat-to-target" strategy, based on values of specific quantitative measures indicating low activity or remission. Tight control leads not only to improved outcomes but also to longer survival, although improvement in mortality rates remains less established and recognized in RA, (11-13) compared to hypertension (14) and diabetes. (15)

While hypertension and diabetes provide many lessons for "treat-to-target" in RA and many chronic diseases, (10) RA differs from hypertension and diabetes in at least five important respects (Table 2):

1. RA is not characterized by a single "gold standard" measure, such as blood pressure, glucose, or hemoglobin A1c, which appears informative in all individual patients. Therefore, pooled indices (16,17) of several measures are needed for standardized quantitative measurement, based on a Core Data Set (18) of seven measures (Table 3).

2. RA rarely is associated with acute emergency situations, such as malignant hypertension or diabetic ketoacidosis. This may contribute to underestimation of the natural history of RA, which is similar to that of hypertension and diabetes, including higher mortality rates than in the general population. Furthermore, most inflammatory rheumatic diseases, such as systemic lupus erythematosus and vasculitis, have a prognosis for premature mortality even far poorer than seen for hypertension and diabetes, (19,20) although this remains unknown to most health professionals and the general public.

3. A patient with chronic hypertension or diabetes (or many other medical conditions) visits a doctor in an outpatient setting to learn from the doctor how she or he is doing, as determined by the "gold standard," quantitative, "scientific" measure. By contrast, a patient with RA (and many rheumatic diseases) visits a physician to tell the physician how she or he is doing.

4. Clinical decisions in patients with hypertension or diabetes are based on vital signs or laboratory tests. Therefore, the patient history and physical examination may be recorded as "subjective" and often ignored narrative descriptions. By contrast, patient history and physical examination information guides clinical decisions in patients with RA. This information should be recorded as quantitative, standardized "scientific" data, using patient questionnaires and formal joint counts.

5. As patient global status is included in all RA indices, patient mood or distress beyond the primary dysregulation may directly affect quantitative data used to guide therapy in "treat-to-target" strategies in RA, but not in hypertension and diabetes. The contribution of patient mood or distress may be assessed through three global estimates completed by health professionals, concerning inflammation, damage, or neither inflammation or damage as a basis for symptoms.

These five differences between the three diseases have important consequences for the format of a treat-to-target strategy in RA compared to hypertension and diabetes, as discussed below:

1. Absence of a Single "Gold Standard" Measure in RA

The absence of a single "gold standard" measure in RA has been addressed with a Core Data Set (18) of seven measures (Table 3): three from a patient self-report questionnaire --physical function, pain, and global status; three from a health professional--number of swollen joints, number of tender joints, and the physician's estimate of global status; one laboratory test, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP); and a radiograph only if a clinical study continues for longer than 1 year.

The most prominent RA index is the disease activity score 28 (DAS28) (21,22) (Table 3), which is the most specific index for RA, (23) and has been the quantitative indicator in all studies to document the value of a "treat-to-target" strategy in RA. (1-9) However, several limitations are seen in scoring the DAS28 in usual clinical care: a. need for a laboratory test, ESR or CRP, which often is not available at the time of the clinical encounter and is normal in about 40% of people with RA at presentation in recent years, (24) b. need for a computer or (excellent) website to calculate scores, based on mathematical weightings for different measures (21); and c. need for a formal tender and swollen joint count, which is not performed at most rheumatology visits. (25)

The clinical disease activity index (CDAI) (Table 3) substitutes a physician global estimate of status (DOCGL) for the laboratory test, (26) and involves simple calculations. Nonetheless, the CDAI requires a formal joint count. An index of only patient self-report scores without formal joint counts, termed RAPID3 (routine assessment of patient index data), is discussed below (see point 3, below).

2. Rarity of Acute Emergencies Attributed to RA

The rarity of acute emergencies may contribute to a substantial underestimation of the long-term severity of the natural history of RA, including high levels of work disability (27) and premature mortality. (28) Patients with RA who have poor physical function or many involved joints have a projected survival over 5 years comparable to three-vessel coronary artery disease or stage IV Hodgkin's disease. (29) The relative risk of dying associated with poor function or high number of involved joints is in the range of (or higher than) hypertension, smoking, or elevated cholesterol. (30) Therefore, rheumatic diseases may have outcomes as severe as seen in cardiovascular or neoplastic diseases, although this reality is not widely recognized by most health professionals or the general public.

The near absence of acute emergencies in RA emphasizes the importance of long-term studies of the natural history and results of treatment over at least 5 years. Short-term data, even over 1 year, are not necessarily applicable to 5-year results. For example, methotrexate appears in systematic studies over 1 year to be comparable to other DMARDs in efficacy and adverse events, not only in a report from 1990, (31) but in a more recent systematic review reported in 2008. (32) By contrast, longer term studies indicate that methotrexate is clearly more likely to be continued over 5 years than other DMARDs, with greater effectiveness and fewer adverse events. (33,34) Therefore, a long-term perspective must be applied to accurately characterize severity and results of treatment in RA and other rheumatic diseases.

3. Importance of Patient History and Physical Examination Data in RA Compared with Hypertension or Diabetes

In patients with hypertension or diabetes, the patient history and physical examination may be recorded in a narrative "gestalt" (even haphazard) format, as clinical decisions are based primarily on a vital sign or laboratory test. The primary patient history information crucial to clinical decision-making concerns adverse events of medications. By contrast, in patients with RA, information from a patient history and physical examination provides the primary information in clinical decisions, reflected in the RA Core Data Set (Table 3), which includes three measures from a patient history, three from a physical examination, and only one from a laboratory test. (18) Nonetheless, the primary (and often only) quantitative measures included in the medical records of most RA patients are laboratory tests, the limitations of which led to a need for indices in the first place.

4. A Standardized, Quantitative "Scientific" Patient History and Physical Examination: Patient Questionnaires and Joint Counts

A patient history may be collected in a standardized, quantitative "scientific" format as a patient questionnaire. A physical examination may be collected in a standardized, quantitative "scientific" format as a formal joint count. Collection and recording of patient history and physical examination information as standardized, quantitative "scientific" data in RA may be regarded as analogous to performance of laboratory tests in diabetes or hyperlipidemia.

Patient questionnaire scores for physical function (28,35) and formal joint counts (28;30) predict work disability and premature mortality, the two undisputed severe outcomes of RA, which have considerably higher levels of significance than laboratory tests, radiographs, or ancillary studies. However, a formal joint count is not included by most rheumatologists at most visits of patients with RA, (25) although a careful joint examination is performed by most rheumatologists at most visits. Therefore, asking a patient to complete a patient questionnaire at each visit in the infrastructure of care appears worthwhile at all rheumatology settings. (36) A patient questionnaire does not preclude collection and recording of a formal joint count, radiograph, laboratory tests, or any other clinical or research measure.

5. Possible Impact of Patient Mood or Distress Beyond the Dysregulation of Inflammatory Activity on "Treat-to-Target" Measures in RA

A patient global estimate of status is included in widely used RA indices, including DAS28, CDAI, and RAPID3.

This measure may be affected directly by patient mood and distress that is unrelated to the level of dysregulation, based on good or bad personal or general events or news. Possible effects of mood or distress on a patient global estimate could have a direct impact on an index designed to guide "treat-to-target" management decisions.

The problem of direct effects of mood or distress on a "treat-to-target" measure is not seen in hypertension or diabetes. Of course, patient mood and distress may affect dysregulation in any disease over long periods, causing an increase in measured severity as blood pressure, glucose, or hemoglobin A1c, but not directly. This matter is of particular relevance in RA, as 20% to 30% of patients with RA are affected by fibromyalgia (37,38); most of these patients have high scores for patient global estimate as well as for the number of tender (but not swollen) joints.

The impact of patient mood and distress appears most relevant to RAPID3, the index of only patient measures (Table 3). However, these variables may also affect DAS28 and CDAI values. Three examples of patients with fibromyalgia who have high activity according to DAS28, CDAI, and RAPID3 are presented in Table 4 (fibromyalgia patients 1, 2, 3). For example, a patient with no swollen joints, an ESR of 18 (indicative of no inflammation), but a patient global estimate of 10, and 28 tender joints [indicative of fibromyalgia (see Table 4, fibromyalgia patient 1)], would have a DAS28 of 6.45 and CDAI of 38, as well as a RAPID3 of 21--all suggesting high disease activity. Even a patient with a tender joint count of 14 and ESR of 10, no swollen joints, and patient global estimate of 10 (see Table 4, fibromyalgia patient 2) would have a DAS28 of 5.11, CDAI of 27, as well as a RAPID3 of 21. By contrast, a patient with RA who has 20 or 28 swollen joints, but no tender joints, (Table 4, RA patients 4, 5) could have a DAS28 score of less than 5.1, suggesting that the patient does not have high disease activity, although CDAI and RAPID3 would suggest high activity. Finally, a patient with lymphoma, who has 4 tender but no swollen joints (see Table 4, lymphoma patient 6), could have high activity according to all three indices. These data indicate the need for interpretation of all index data (and all clinical measures) by a knowledgeable and caring health professional in formulating clinical decisions.

The impact of mood and distress on RA indices may explain, in part, why very few clinical sites report more than 30% of patients meeting "remission" criteria of a DAS28 less than 2.6 or CDAI less than 3. One approach to analyzing mood and distress is for a health professional to assign, in addition to an overall global estimate, three additional global estimates for a. the level of inflammation, b. level of joint damage, and c. level of symptoms not due to inflammation or joint damage (often due to fibromyalgia). The physician global estimate of status generally has higher relative efficiency than joint counts to distinguish active from control treatments in clinical trials and is much more simply assigned. (39)

The four physician global estimates can be combined with six scores from patient self-report for physical function, pain, global estimate of status, fatigue, number of symptoms on an MDHAQ, and RAPID3 (a composite of physical function, pain, and global estimate) to provide a checklist of 10 quantitative measures. The concept of a checklist has been developed by Gawande and colleagues in surgical practice, (40,41) and may be applicable to all medical care to review matters in complex situations that may otherwise be overlooked. A proposed checklist of 10 measures for RA (and other rheumatic diseases) requires only 15 seconds, and may assure quantitative data on each patient at each visit.

Conclusion

This essay summarizes important similarities and differences between RA, as compared to hypertension or diabetes, and consequences for rheumatology care. In hypertension and diabetes, data from vital signs and laboratory tests guide clinical decisions, and the patient history and physical examination may be recorded in a narrative and even haphazard format. However, the importance of the patient history and physical examination in RA requires recording as standardized, quantitative "scientific" data in the format of a patient questionnaire and formal joint count. Since formal joint counts are not performed at most visits, completion of patient questionnaire assures quantitative data at each visit. Physical examination information can be captured as quantitative standardized data with four physician global estimates: a global estimate of overall clinical status and three additional estimates concerning inflammation, damage, and no inflammation-no damage as the basis for symptoms. A 15-second checklist of patient questionnaire and physician global scores can assure quantitative data in the infrastructure of care at each rheumatology visit.

Disclosure Statement

Isabel Castrejon, M.D., has no financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony. Theodore Pincus, M.D., has received consultant fees and lecture fees from Bristol-Myers Squibb. He has received consultant fees from and served on a Scientific Advisory Board for UCB, Inc. He has received research support from Centocor, Inc.

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Isabel Castrejon, M.D., and Theodore Pincus, M.D., are from the Division of Rheumatology, Department of Medicine, NYU Hospital for Joint Diseases, NYU Langone Medical Center, New York, New York. Dr. Pincus is Clinical Professor of Medicine, NYU School of Medicine.

Correspondence: Theodore Pincus, M.D., Room 1608, Division of Rheumatology, NYU Hospital for Joint Diseases, 301 East 17th Street, New York, New York 10003; tedpincus@gmail.com.
Table 1 Similarities of Rheumatoid Arthritis, Hypertension, and
Diabetes

1. Dysregulation of normal physiologic functions

2. Persistent dysregulation results in long-term organ damage, to
musculoskeletal, cardiovascular, and other systems

3. Damage generally correlated over time with clinical severity

4. Etiology of the dysregulation remains unknown

5. No cure available

6. Medications available to control dysregulation

7. Control of dysregulation slows or prevents organ damage

8. Optimal prevention of organ damage requires "tight control"
beyond simple improvement

9. Tight control leads to improved outcomes, including longer
survival

Table 2 Some Differences Between "Treat-to-Target" Approach in
Hypertension and Diabetes Compared To Rheumatoid Arthritis

                       Hypertension and       Rheumatoid Arthritis
                       Diabetes

1. Quantitative        "Gold standard"        Pooled index:
measure of clinical    quantitative,
status                 objective measure:     * Core Data Set

                       * Blood pressure       * DAS28

                       * Glucose              * CDAI

                       * Hemoglobin A1c       * RAPID3

2. Presentation as     May be seen as:        Rare emergency:
acute emergency                               e.g., vasculitis

                       * Malignant            Severity and long-
                       hypertension           term consequences in
                                              natural history are
                       * Ketoacidosis         underestimated

                       Acute emergency
                       presentation
                       contributes to
                       recognition of
                       morbidity and
                       premature mortality

3. Doctor-patient      Patient seeks          Patient tells doctor
interaction at         information to learn   how she/he is doing,
medical encounter      how she/he is doing,   according to history
                       according to gold      and physical
                       standard measure       findings

4. Medical history     May be collected as    Should be collected
and physical           nonquantitative,       as standardized,
examination            narrative,             quantitative,
information            descriptive notes      scientific patient
                                              questionnaire and
                                              joint count data

5. Patient mood and    No direct acute        May have direct
distress               effect on measure of   effect on measures
                       dysregulation used     used in "treat-to-
                       in "treat-to-          target" strategy,
                       target" strategy,      independent of
                       though may have        dysregulation,
                       indirect effect on     particularly as
                       measure over time      fibromyalgia occurs
                                              in 20% to 30% of RA
                                              patients

Table 3 Measures Included in Indices to Assess Patients with
Rheumatoid Arthritis

                                      ACR Core
                                      Data Set
                                        (18)        DAS28 (21,22)

Physician-Assessed Measures

  Tender joint count (TJC)            [check]    0.28 x sq rt (TJC28)
  Swollen joint count (SJC            [check]    0.28 x sq rt (SJC28)
  Physician global estimate (DOCGL)   [check]             --

Laboratory Measure

  ESR or CRP                          [check]      0.70 x ln (ESR)

Patient-Reported Measures

  Patient function (MDHAQ-FN)         [check]             --
  Patient pain                        [check]             --
  Patient global estimate (PATGL)     [check]       0.014 x PATGL
  Total score range                      --              0-10

                                       CDAI    RAPID3
                                       (26)    (42,43)

Physician-Assessed Measures

  Tender joint count (TJC)             0-28      --
  Swollen joint count (SJC             0-28      --
  Physician global estimate (DOCGL)    0-10      --

Laboratory Measure

  ESR or CRP                            --       --

Patient-Reported Measures

  Patient function (MDHAQ-FN)           --      0-10
  Patient pain                          --      0-10
  Patient global estimate (PATGL)      0-10     0-10
  Total score range                    0-76     0-30

Table 4 Quantitative Measures for Patients with Rheumatoid
Arthritis. A Comparison of Values in Patients with Fibromyalgia,
Rheumatoid Arthritis, and Lymphoma

                      Physical
Pt                    Function      Pain        PATGL       DOCGL
No.    Diagnosis       (0-10)      (0-10)      (0-10)      (0-10)

1      Fibromyalgia       1          10          10           0
2      Fibromyalgia       1          10          10           3
3      Fibromyalgia       1           8           8           3
4      RA                 4           6           3           2
5      RA                 4           6           3           2
6      Lymphoma           4           5          10           8

                                                 ESR
Pt                      TJC28       SJC28      (0-150
No.    Diagnosis       (0-28)      (0-28)       mm/h)

1      Fibromyalgia      28           0          20
2      Fibromyalgia      14           0          10
3      Fibromyalgia      24           0          20
4      RA                 0          20          50
5      RA                 0          28          50
6      Lymphoma           4           0         100

Pt                     RAPID3       CDAI        DAS28
No.    Diagnosis       (0-30)      (0-76)      (0-10)

1      Fibromyalgia      21H         38H        6.45H
2      Fibromyalgia      21H         27H        5.11H
3      Fibromyalgia      17H         35H        5.95H
4      RA                13H         24H        4.43M
5      RA                13H         32H        4.67M
6      Lymphoma          19H         22H        5.75H

H, high disease activity; M, moderate disease activity. PATGL,
patient global estimate of status; DOCGL, physician global estimate
of status; TJC, tender joint count; SJC, swollen joint count; ESR,
erythrocyte sedimentation rate; RA, rheumatoid arthritis.
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