Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

JOURNAL CLUB - Rheumatology

December 2010

Based on Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010;69(4):631-7

and

Presentations from the 2010 Annual European Congress of Rheumatology (EULAR) Rome, Italy / June 16-19, 2010

Editorial Review:

Edward C. Keystone, MD, FRCPC, Director, The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease Director, Division of Advanced Therapeutics in Arthritis Chair, Canadian Rheumatology Research Consortium Consultant (Rheumatology), UHN-Mount Sinai Hospital Professor of Medicine University of Toronto Toronto, Ontario

Studies have shown that joint erosions occur early in rheumatoid arthritis (RA) and that over 90% of patients with <2 years’ disease duration may have radiographic abnormalities, radiographic progression being more rapid in the first year of disease. In fact, erosions can be detected within 4 months of disease onset with magnetic resonance imaging.

Early Intervention

In 2004, Canadian experts issued a consensus statement on optimal therapy in early RA in which they discussed the rationale for early intervention (Ann Rheum Dis 2004;63(2):149-55). They emphasized early intervention and rapid disease control with the use of disease-modifying antirheumatic drugs (DMARDs) and novel biologic agents targeting tumour necrosis factor (TNF) to slow progression of joint erosion and subsequent functional loss.

The just published European League Against Rheumatism (EULAR) recommendations for the management of RA with synthetic and biologic DMARDs state that treatment with synthetic DMARDs should begin as soon as the diagnosis of RA is made, as any treatment delay may lead to a worse outcome in comparison with an early initiation of therapy. Since diagnosis in its earliest stage is difficult, a suspected diagnosis may be sufficient to initiate DMARD treatment (Ann Rheum Dis 2010;69(6):964-75).

For example, updated data from COMET (Combination of Methotrexate and Etanercept in Editorial Review: Studies have shown that joint erosions occur early in rheumatoid arthritis (RA) and that over 90% of patients with <2 years’ disease duration may have radiographic abnormalities, radiographic progression being more rapid in the first year of disease. In fact, erosions can be detected within 4 months of disease onset with magnetic resonance imaging. Active Early Rheumatoid Arthritis) support very early intervention. Findings showed that almost 70% of patients with RA (n=63) who were treated =4 months of their diagnosis with methotrexate (MTX)/etanercept achieved clinical remission compared with 48% of those who were treated >4 months after their diagnosis (EULAR 2010, Abstract LB0001). Also published are recommendations of an international task force on treating RA to target (Ann Rheum Dis 2010;69(4):631-7). The recommendations build on early intervention with the concept of tight disease control, aided by objectively measured targets of remission or low disease activity (LDA) and frequent monitoring of treatment response to ensure targets are met.

Tight Control: A New Concept in RA

The concept of tight control, defined as treating patients to specified targets with aggressive therapy if necessary, has been widely promoted in the management of hypertension and diabetes. In the management of RA, the idea of controlling inflammation to set targets is a new concept.

A review of the value of tight control evaluated intensive management of patients using a predefined disease activity target (J Rheumatol 2010;37:1570-8). In the review, one of the first studies to clearly illustrate superiority of intensive management with routine disease activity assessment was the TICORA study (Lancet 2004;364:263-9). In TICORA, patients were assigned to 1 of 2 groups; one group consisted of intensely managed patients with active RA who saw a rheumatologist every month; those who had not achieved a disease activity score (DAS) =2.4 at every assessment after month 3 had the dose of their oral therapy increased or another drug added.

The second group was assigned to routine care and were supervised in the usual rheumatology clinics where, while reviewed every 3 months, treatment response was not formally assessed by any composite measure of disease activity. Over the course of 18 months, patients assigned to the intensive care group had significantly lower mean disease activity scores from month 3 onward compared with the routine care group (P<0.0001) (Figure 1). Of the intensive management group and routine care patients, remission (DAS<1.6) was reported in 65% vs. 16% and a good response, defined as a decrease in DAS=1.2, in 82% vs. 44%, respectively (both P<0.0001).

With accumulating evidence in support of tight control, the EULAR international task force emphasized that achieving treatment targets of remission or LDA early will lead to better structural and functional outcomes as well, and the earlier such a state is achieved, the better.

Two recent studies support achieving early remission or LDA. A post-hoc analysis of ASPIRE (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset) showed that attainment of remission at 3 months with MTX halted progression of joint damage between baseline and one year (Ann Rheum Dis 2009;68:823- 7). Remission and LDA at month 3 in the AIM (Abatacept in Inadequate Responders to Methotrexate) study also predicted low levels of radiographic progression at one year (Arthritis Rheum 2009;60(Suppl 10):1691).

Figure 1.

Frequent Monitoring and Treatment Adjustments

Achieving remission or LDA through strict monitoring and treatment adjustment has been associated with better clinical, radiographic and functional outcome. Based on evidence to date, the 2010 EULAR task force recommended that treatment be aimed at reaching remission or LDA as soon as possible in every patient and that treatment be adjusted by frequent (every 1 to 3 months) strict monitoring if the target has not been reached. Also, the routine use of valid clinical indices of disease activity such as the DAS, DAS28, Simplified Disease Activity Index (SDAI) or the Clinical Disease Activity Index (CDAI) is recommended for monitoring.

Concerning treatment adjustments, the EULAR task force recommended that patients failing on synthetic DMARDs be initiated on a TNF inhibitor in combination with MTX or other DMARDs since combination therapy is more effective than monotherapy. The task force also strongly felt that for patients with unfavourable prognostic signs, including very active disease or early structural damage, first-line biological treatment wi
idered.

Figure 2.

<img4710|center>

Rapid Control Predicts Long-term Prognosis

The ability to rapidly determine treatment efficacy is intricately linked to improving long-term prognosis. Maximal ACR20 responses can be reached as early as 12 weeks following initiation of a combination of MTX/ certolizumab pegol, thus allowing physicians and patients to more accurately predict long-term responses to treatment. Frequent monitoring and treatment adjustments are also important factors contributing to the efforts to attain earlier remission or LDA.

Findings from the DREAM (Dutch Rheumatoid Arthritis Monitoring) registry, for example, showed that the sooner patients achieved their first remission, the higher the chance of sustainability of that remission. In this registry, the median time to remission for those achieving sustained remission was 9 months vs. 14 months for those who did not. Thus, even in established RA, the earlier the initiation of a TNF inhibitor, the better (EULAR 2010, Poster SAT0046).

In Hallert et al. (EULAR 2010, OP0040), patients with early RA who achieved an LDA (DAS28 <3.2) 3 months after diagnosis were significantly less likely to take sick leave or early retirement between years 1 and 4 following their diagnosis than those whose score was =3.2. Also in the same cohort, DAS28 at 3 months was a good predictor of disease activity, functional capacity as measured by the health assessment questionnaire (HAQ) and quality of life.

A recent follow-up of patients from the RAPID 1 (Rheumatoid Arthritis Prevention of Structural Damage) study of MTX/ certolizumab pegol showed that those who achieved a rapid and more pronounced response to treatment by week 12 were more likely to remain in LDA 2 years later, compared with patients who had a slower or less robust response to treatment (EULAR 2010, Abstract SAT0059). By week 12, the majority of patients at 86.7% had achieved a DAS28 improvement of 1.2 units from baseline (Figure 2).

Almost 80% of the same cohort had achieved a EULAR good/moderate response at week 12 while 88% and 89% of the group reached the same end points at 1 and 2 years of follow-up. At 2 years, 35.2% of the original intent-to-treat (ITT) population had achieved LDA.

Importantly, patients who achieved an earlier DAS28 =1.2-unit response during the first 12 weeks of treatment were more likely to have LDA at both years 1 and 2 than patients who responded later. For example, 44.3% of week 1 DAS28 1.2-unit responders had LDA at years 1 and 2 vs. 29.7% of week 12 DAS28 1.2-unit responders. Almost 30% of patients who had achieved a DAS28 1.2-unit response by week 12 had LDA at both years 1 and 2 compared with only 1.9% of DAS28 1.2-unit nonresponders at week 12. Thus, as investigators observed, a lack of DAS28 response during the first 12 weeks of treatment was “hig
ilure to achieve LDA at both years 1 and 2 (Table 1).

Table 1.

<img4711|center>

These findings have important clinical implications. Peak ACR50 responses have been reported as early as 14 weeks for the newer anti-TNF agents such as certolizumab pegol and golimumab. The early onset of ACR response with certolizumab pegol combined with the DAS-driven predictability tools outlined makes it an attractive choice when initiating TNF inhibitor therapy. Should a lack of adequate response be evident by week 12, in a population of patients with high disease at initiation of therapy, switching to an alternative treatment regimen may provide patients with the ability to move on to a more suitable therapy with a minimum of delay.

Summary

The new EULAR recommendations represent an important shift from routine RA care towards one that can essentially be considered patient-centred. Given that preservation of joint function and limitation of functional disability is the most important goal in RA management, the cornerstones of RA management today include early intervention at the time of diagnosis and rapid and measurable disease control with frequent monitoring of treatment response with intent to switch therapy if patients do not achieve targets early on. Rapid response is also predictive of sustained response, which is another important concept in the modern management of RA. The availability of highly effective DMARDs makes this treatment paradigm possible and with their judicious use, physicians should change the way RA affects not only individual patients but society as a whole.

questions and answers

Panel

Majed Khraishi, MB, BCh, FRCPC Memorial University of Newfoundland St. John’s, Newfoundland and Labrador

Denis Choquette, MD, FRCPC, FMSQ, Institut de rhumatologie de Montréal Montreal, Quebec

Janet E. Pope, MD, MPH, FRCPC, University of Western Ontario London, Ontario

Robert C. Offer, MD, FRCPC, University of British Columbia Vancouver, British Columbia

What are the greatest barriers to the widespread use of validated composite measures such as DAS28/SDAI/CDAI?

Dr. Khraishi: Most rheumatologists in Canada recognize the importance and the need to use targeted outcomes as a part of RA management. However, I believe time constraints and the use of more traditional outcomes (e.g. joint count) as an entrenched way of measuring disease activity restricts the wide implementation of the DAS and the newer outcomes.

Dr. Offer: Time. Most community rheumatologists are overwhelmed by the number of forms, requisitions and letters required to care for a patient with chronic inflammatory arthritis. Composite measures may be validated in academic centres but they are yet another form or calculation that takes time. Many practicing rheumatologists are not convinced that a composite measure will influence their therapeutic decisions. CRP or ESR results are often not available at the time the patient is being seen and treatment changes are being considered. The clinical assessment without the current acute phase reactant or calculated composite measure is often adequate to make treatment decisions. This does not apply to the CDAI which can be calculated without any lab results. Despite being a valid outcome measure in clinical trials, at the individual patient level, the DAS28 is an unsatisfactory guide to therapy as it emphasizes tender joints over swollen joints, does not include many joints important to the patient (ankles, feet, temporomandibular joints, C-spine), and ignores other important disease features such as fatigue and nodules. Overall, the use of composite outcome measures has never been shown to be superior to frequent and thorough follow-up by a rheumatologist.

Dr. Pope: There are barriers with respect to composite measures being routinely performed in the clinic for patients with RA. Some of the measures may lack face validity in routine practice; there are problems calculating scores such as the DAS in a busy practice; and it takes time to perform and calculate composite scores. For the DAS, SDAI and CDAI, many rheumatologists think that the tender joint count (TJC) may not be due to active joints and thus “discount” it. Several Canadian rheumatologists have said they do components of composite scores but often they change treatment if there are swollen joints or if the physician global score is high. The DAS was developed from chart audits of where physicians would change treatment, but many doctors change treatment in RA based on the swollen joint count (SJC), especially if the joints are thought to be subacute as opposed to chronic pannus.

Dr. Choquette: The biggest barriers are ignorance that [these composite measures] have very significantly improved the short term and most importantly the long term outcomes of patient with inflammatory arthritis, [and the] impression that their use is time-consuming and not necessary in standard clinical practice. The last statement may be true when the rheumatologist begins to use them in clinical practice but with time, this obstacle very rapidly becomes an advantage for the practitioner and the patient. DAS measures may be more complicated to implement in practice but SDAI, and especially CDAI, is a simple addition of clinical variables which is certainly not cumbersome in practice.

What outcome measures can be used in daily practice for the “treat-to-target” strategy? Is there an optimal target?

Dr. Khraishi: CDAI, TJC and SJC in addition to the DAS 28 (ESR or CRP) are all reasonable and achievable outcome measures. In my opinion, the most important point is to use a specific outcome measure and use it consistently. In some provinces the DAS and the ACR responses are required to renew biological therapies.

Dr. Offer: The optimal target is remission. Strict definitions of remission exist for research and trial purposes. However, in day-to-day practice, remission means absence of all signs and symptoms of RA, including swollen and tender joints, stiffness and fatigue, and extraarticular and laboratory parameters. In the long term, remission also requires the absence of radiologic progression. Research criteria will never be as meaningful in daily practice as a thorough history and examination. In time, we will undoubtedly need to incorporate ultrasound or MRI into our daily decisionmaking. A thorough but flexible clinical assessment of the patient is more meaningful than a number rigidly arrived at by adding up joint counts and scales performed by an office assistant. “Treat-to-target” or “tight control” studies make important conclusions regarding ideal strategies in academic centres, but they are not necessarily relevant to community rheumatology practices where many rheumatologists follow patients intensively in the early months of disease with remission as the target.

Dr. Pope: The optimal target is not known, just as the best measurement is not known for routine practice in Canada. The target should be absence of inflammation within the joints (i.e. true remission) and if not achievable, then a low disease state should be targeted. The low disease states for SDAI and CDAI are closer to remission than a low DAS where the SJC could be substantial in some patients with a low DAS. It is relatively easy to do TJC, SJC, physician and patient global assessments and inflammatory markers; also, the HAQ and pain scale can easily be performed. Whatever the target, it should be the best state achievable for each patient, so at times the target is individualized. Someone with pain not due to RA may always score poorly on their global assessment but have inactive RA. Thus the scores must be interpreted within the context of the patient encounter.

Dr. Choquette: All the validated scores can be used in clinical practice. At the Institut de rhumatologie de Montréal, we are fortunate to have the Rhumadata software that calculates all DAS scores, CDAI and SDAI by simply entering SJC and TJC, CRP and ESR values. Patients themselves input their global and HAQ questionnaire responses. But for any rheumatologist, a simple follow-up of at least the TJC and the SJC aiming at a score of zero should be acceptable. Remission is the target and optimization of all aspects of the treatment (baseline DMARDs and biologic therapies) should be done on regular and at short fixed intervals at the initiation of therapy.

What is the role of the patient in driving clinical outcome assessment?

Dr. Khraishi: The patient is the centre of our management plans. As I tell my students: “We treat patients, not diseases.” The more patients understand the serious consequences of suboptimal treatment, the more they become active partners in monitoring their disease progress and choice of therapy. Tools that can be easily scored and administered by patients can be widely utilized. An example of that is now employed by us in psoriatic arthritis. On the psoriatic arthritis screening questionnaire (PASQ), patients can mark on an electronic Web page or application which joints are involved followed by a simple questionnaire that can be scored electronically. Such tools can be easily conveyed to rheumatologists and reduces the time needed to make assessments.

Dr. Offer: Clearly, many components of commonly used outcome measures are driven by subjective patient measures including the patient global, TJC, morning stiffness, DAS28, HAQ and BASDAI. Such measures may therefore be markedly influenced by patient factors such as coping skills, anxiety, depression or concurrent fibromyalgia. In contrast, the physician global assessment has has been shown to be a much more reliable outcome measure. Following an outcome assessment, oftentimes the patients whose RA is only partially controlled will decline further changes to their treatment program due to past (and feared) side effects.

Dr. Pope: Patients are often used to having a chronic disease and may be fearful of treatment side effects. By adapting to swollen joints, especially if the pain level is not high, they may not want to make a change. In addition, sometimes the treatment goals are disparate: patients who are subluxed at their metacarpophalangeal (MCP) joints want to have their function return to normal (which will not occur with medical treatment), or someone without a painful joint usually does not want it injected even if told that it may prevent damage. Also, patients may want to have no pain whereas the physician may determine that the flare of pain is not from active RA but from other problems such as mechanical back pain. The most difficult treatment change discussion is when there is a mismatch of expectations between the patient and the physician. However, without offering a change in treatment and without targeting an outcome, the outcome is reached less often. Thus, explaining the reasons for treatment changes can often educate patients and allow them to be better partners in their care.

Dr. Choquette: The role of the patient is certainly to be an active partner in taking charge of the evaluation and treatment of their disease. An educated patient will perform better over the long term. He will certainly better understand the importance of adhering to his therapeutic regimen which is an area of uncertainty at the present time. At the last ACR, a poster showed that a very significant proportion of patients with RA stop taking their MTX while on biologic therapy, although the combination has been shown to improve the radiological outcome in particular. This [reveals] a serious educational gap that should be addressed in the future.

What is the most common followup regimen used by rheumatologists when initiating (synthetic biological) DMARD therapy?

Dr. Khraishi: I tend to see patients within 2-3 months after starting a DMARD with inflammatory markers (ESR or CRP) and then every 3-6 months depending on the progress, response and individual needs of the patient. In areas where there are more rheumatologists available, I believe the follow-up visits are done at shorter intervals.

Dr. Offer: Follow-up depends primarily on the level of disease activity (more active RA usually results in more frequent visits) and on the DMARD prescribed. Typically hydroxychloroquine, doxycycline and biologics are followed up around the 12th week unless the patient reports a problem in the meantime; most rheumatologists follow MTX, leflunomide, azathioprine, cyclosporine or gold monthly until stable, then reduce the frequency of follow-ups. Follow-up includes appropriate labs, clinical assessment and more time to consider comorbidities such as cardiovascular risk factors or bone health.

Dr. Pope: For any change in treatment, patients are seen to determine if the treatment has started to help and to ensure that there are no worrisome side effects. Because biologics work quickly, patients are often seen back in 2 to 3 months and once the target has been achieved, they are often seen far less often and may actually utilize health care less when in sustained remission.

Dr. Choquette: The ideal usual follow-up regimen should be one that very rapidly evaluates patients with inflammatory arthritis at its onset. Treatment should be instituted very early as it improves response and permits long-term control of disease activity. An initial combination of traditional DMARDs such as MTX at a minimum dose of 20 to 25 mg/week and hydroxychloroquine and/or [sulfasalazine] is also preferable for clinical and administrative reasons. Follow-up evaluation of response to treatment should be performed at a maximum of 2- to 3-month intervals. Failure to maximally respond by reaching remission or at least low disease activity score should trigger an adjustment of treatment or the introduction of a newer biologic agent.

Can rheumatologists predict the response to synthetic and biologic DMARD treatments? What are the recommendations for partial responders?

Dr. Khraishi: At this stage, we cannot make such predictions with certainty; however, we have reasonable predictors of response and progress of disease such as high CRP, positive rheumatoid factor (RF) and anti-CCP. Previous failure to respond to multiple DMARDs makes it less likely to have a good response with newer agents.

Dr. Offer: One of the major challenges in modern-day rheumatology is predicting the right treatment for a specific patient. There are many drugs acting through different mechanisms of action and many variations in rheumatoid pathogenesis but few guides to help us decide which therapy will be effective and safe in a particular patient. Disease activity at baseline (CRP, SJC) is generally an important predictor of response. While the greatest degree of response occurs in patients with the highest disease activity, the greatest chance of remission occurs in patients who have low disease activity. The British Registry showed responses to anti- TNF therapies were reduced in patients who were more disabled, RF-positive and anti-CCPpositive. In other words, a lower HAQ and seronegativity predict a better response to anti-TNFs. However, the BeST study showed no relationship between titre of anti-CCP and response. Several single nucleotide polymorphisms have been associated with therapeutic responses but are not clinically available. From a practical point of view, no predictor is accurate for an individual patient at this time. For rituximab, it is clear that a positive RF predicts better outcomes compared to a negative RF. However, even this relatively strong observation is of limited use in individual prescribing, as seronegative patients still have a significant chance of achieving a high level of response compared to placebo. Partial responders, the majority of our patients, represent the most difficult decisions in modern rheumatology, given the multiple therapies now available. After removing remitted and nonresponder patients from the total number started on a biologic, the remaining 60% majority are partial responders (the “ACR un-70” and “ACR un-50” patients). Strategies for this group include acceptance of less than complete remission; adding or intensifying concomitant DMARDs; escalating the biologic; or switching the biologic. The latter is done without any reliable predictor that the next biologic will perform any better and a host of studies show reduced responses to subsequent biologics. Many factors come into play including adherence, comorbidities, safety data and currently inadequate predictors of success following switching.

Dr. Pope: We can predict that those in a high disease state may take longer to achieve remission than those in a moderate state (on average, but we cannot necessarily predict within individuals). There are biomarkers of good responders but they are only weakly associated and include patient and lab factors, such as lack of smoking, good adherence, moderate (vs. high) disease state and, for some medications, a positive RF may have a better response than a negative RF. We can’t predict easily within an individual how well they will respond to a particular biologic but the faster the onset of a clinically relevant benefit, the better the response at 1 year (i.e. 3 months may predict the 1-year disease state). The first biologic is usually the best with respect to both response and durability of response. We do not have a rational recipe for what to use within each individual and in what order and—in some cases—at what dose. Partial responders should still be targeted to obtain remission or a low disease state. If someone has had a great improvement with treatment but is still not in a low disease state, then several options exist, including following the patient to determine if the low disease state is achieved at the next follow-up, injecting active joints with steroids or giving intramuscular or oral steroids, enhancing the DMARDs (dose, route of administration, adding a new DMARD) and rarely changing the biologic (or in the case of infliximab, increasing the dose). Thus partial responders are heterogenous and it depends on what disease state they are in (i.e. moderate to low), at what time point they are assessed, at what stage of their disease they are in, what is thought to be achievable and what comorbidities are present.

Dr. Choquette: Several recent data have shown that early initial response predicts long-term outcome, and this is especially true with patients evaluated early at the onset of their disease. There are administrative limitations to the use of such information, as some private and public insurance plans do not permit drug changes before 5 to 6 months of trial. Some agents are also still not reimbursed. Other plans also cover treatment only after failure of many more traditional therapies, although the recent data do not support that course of action. Economic considerations are certainly at the basis of such rationale.

What is the benefit for you and your patients if you can predict response to treatment earlier rather than later? Is timing of response predictive of long-term outcome?

Dr. Khraishi: That would be a step in the right direction. It helps us choose the most appropriate drug at an early stage and prevent the serious consequences of progressive nonremittent RA.

Dr. Offer: Patients with a good early response do better long-term than those whose response is much slower. The late responders never catch up in the measures that predict longterm disability such as erosion and JSN scores. A good early response (by 12 weeks) can be particularly helpful with rapidly peaking agents such as certolizumab, as a failure allows the more rapid switch to an alternative and hopefully effective therapy. Some biologics such as abatacept require a much longer period to assess peak response and thus abatacept poor responders may be exposed to a longer period of damaging synovitis before a switch is made. Early responses do predict better long-term outcomes to some extent. However, a rapid response must be combined with a durable response in order to be clinically valuable. For example, infliximab generally acts rapidly but its durability is less predictable than other anti-TNFs.

Dr. Pope: If response to treatment can be predicted early, then the optimal use of a certain product can be determined. For instance, if a patient has had no response at all to a biologic drug at 3 months, then it is very unlikely that the patient will be in a low disease state at 1 year. If this is the first biologic, then changing to another biologic makes sense. However, this is a rare scenario as most patients will have some response by 3 months. If the response is good (e.g. at least a change in DAS of 1.2 or a reduction of 40% in SJC), then it is likely that further improvement may occur by one year. If the response is marginal, the patient should be reassessed by 5 to 6 months and if a substantial change in state has not occurred, then the patient’s treatment should be optimized such as adding or changing therapy. Timing of response is predictive of long-term outcome for biologic drugs. The timing may not be as predictive in slow-acting DMARDs, but even for MTX, if there has not been a good response by 3 months, it is not likely that remission will be achieved at one year. Thus, determining the change in status (treatment response) at 3 months after initiating any treatment in RA will help predict outcomes at one year. Earlier prediction of response allows for optimizing patient care and optimizing the use of any RA treatment including continuing, switching or adding treatment.

Dr. Choquette: The major benefit for the patient would be to be able to select the most appropriate agent early in the disease course. It would improve long-term clinical and functional outcomes and decrease the incidence of adverse events associated with the use of co-therapies such as NSAIDs or corticosteroids. The advantage for the physician is that the better the control of the disease, the simpler the follow-up of those patients. Implementing standard tools such as questionnaires (e.g. HAQ, BASDAI, BASFI) and disease activity evaluation instruments in standard practice generally simplifies patient evaluation.