ACR ARHP. The Need for Patient Assessment Tools for Early Detection of Flares. Individualizing Patient Care in Rheumatoid Arthritis:

Transcription

1 R E P O R T F R O M ACR ARHP 2008 Annual Scientific Meeting Individualizing Patient Care in Rheumatoid Arthritis: The Need for Patient Assessment Tools for Early Detection of Flares CAnadian Vision for Rheumatology

2 Individualizing Patient Care in Rheumatoid Arthritis: The Need for Patient Assessment Tools for Early Detection of Flares Anna Christofides Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune disorder characterized by symmetric inflammation of the joint lining. Untreated, RA can result in damaged cartilage, bone erosions, and inflammation of internal organs. In Canada, RA has a prevalence of approximately 1% in adults and affects about 300,000 (one in 100) individuals. It occurs two to three times more frequently in women than in men, and most often develops between the ages of 30 and 50 years. Within a period of three years after diagnosis, 20% to 30% of people with RA become unable to work if they remain untreated. 1,2 The introduction of tumour necrosis factor inhibitor (TNF-I) therapy has had a significant impact in improving disease outcome. Although aproximately 60% of RA patients respond when they use methotrexate (MTX) in combination with TNF-Is, refractory patients remain difficult to treat. Agents with other mechanisms of action may therefore be of benefit to patients that have an inadequate response (IR) to TNF-Is. 1 Rituximab, an anti-cd20 chimeric monoclonal antibody, has proved to be effective in suppressing disease activity in RA. Randomized trials have demonstrated efficacy both in MTXresistant and TNF-I therapy resistant patients. 1,3 Rituximab is now approved by Health Canada in combination with MTX for use in adult patients with moderate-to-severe active RA after IR or intolerance to >1 TNF-I therapies. 4 As with other biologics in RA, maintenance therapy with rituximab is often required. Despite the success seen with initial rituximab treatment, approximately 50% of patients require re-treatment. However, published evidence for efficacy and safety of repeat treatment courses of rituximab is restricted to data presented at international meetings. Many questions remain unanswered in the use of rituximab for re-treatment in RA. 3 To address these information gaps, an advisory board on rituximab re-treatment was formed that included a group of North American experts in RA. The advisory board meeting took place on Friday, October 24, 2008, during the ACR/AHRP 2008 Scientific Meeting. Individualizing treatment to minimize adverse effects and ensure the best patient care was the overall key message of the meeting. Issues discussed included setting realistic patient expectations for re-treatment, obtaining and using rituximab, establishing frequency and timing of patient appointments, and scheduling infusions. At the advisory board meeting, a group of experts led by Dr. Vivian Bykerk, assistant professor at the University of Toronto and rheumatologist at Mount Sinai Hospital, Toronto, discussed logistic issues with repeat treatment of rituximab. The group identified a need for a patient-driven assessment tool to improve early detection of flares and identify when to re-treat. The tool would aid in the development of a standardized protocol that could be used in clinical practice to address many issues faced in the use of rituximab for RA. Subsequent to the advisory board meeting, New Evidence conducted an in-depth interview with Dr. Bykerk about the proposed patient assessment tool. During the interview, Dr. Bykerk discussed the preliminary content to be included in the tool and how such a tool could aid in solving many of the existing issues with rituximab retreatment. The following article describes some of the key issues faced by rheumatologists in re-treating RA patients and presents some preliminary ideas in the initial development of the patient assessment tool. New Evidence in Rheumatology January

3 Impact of rheumatoid arthritis on quality of life Given the lack of a treatment option that prevents or cures RA, management goals often focus on improving quality of life (QoL) and reducing disability. 5 However, several studies have shown that patients and physicians consider different factors in determining RA severity. Patients tend to focus on symptoms of fatigue and pain, while rheumatologists often examine the number of swollen, rather than painful joints. 6 Persistent pain, fatigue, and depression in uncontrolled RA Pain is often the major concern of patients with RA and is one of the main factors that prompt patients to seek medical attention. 5 Most current RA treatments target pain relief to a greater or lesser extent. However, despite treatment, many patients continue to experience persistent pain. Variations in pain exist across patient groups, with scores distributed over a wide range of severity. Pain levels in RA are similar to those experienced by patients with widespread pain from other causes, but disability levels are higher. Higher pain levels have been shown to correlate with disability as well as depression, which contribute significantly to reduced QoL. Qualitative research shows that RA patients regard fatigue as a major determinant of QoL and believe reducing fatigue should be a key goal of treatment. 5 Clinically significant fatigue is present in 40% 80% of patients, and its absence is one of the key components of remission, the principal therapeutic goal in RA. Depression has been identified as a significant problem for a large proportion of patients with RA. 5 Some studies have suggested that depressive symptoms are present in 25% or more of patients. Depression is associated with reduced health status, as well as higher pain and fatigue levels and reduced QoL. Impact of disease-related symptoms on physical function and quality of life Disability in RA is usually measured with selfassessment questionnaires. Most clinicians use disease-specific measures, such as the Health Assessment Questionnaire (HAQ) or the Arthritis Impact Measurement Score (AIMS). An alternative approach is to use generic measures; these include the Shortform Health Survey (SF-36), the Nottingham Health Profile (NHP), and the EuroQol. 5 Kvien, et al. 7 examined the physical function of 1,030 patients with RA from a Norwegian registry. SF-36 scores were compared with disease-specific health status instruments including a modified version of AIMS (AIMS2), a modified version of HAQ (MHAQ), and Visual Analogue Scales (VAS). (Table 1) The worst score (27.0) using the SF-36 instrument was for role-physical, which measures role limitations due to physical health. Using the VAS and AIMS2, pain was consistently rated as a significant problem. Increased age was associated with increasing health problems in all dimensions. However, the effect of age was less pronounced for mental and affective health, compared with the other dimensions. Table 1. Scores of SF-36 and disease-specific health status measures in 1,030 patients with rheumatoid arthritis* Scales SF-36 (0 100, 0 worst health) Sample Size (%) Mean (SE) Physical functioning (0.83) Role-physical (1.12) Bodily pain (0.69) General health (0.70) Vitality (0.71) Social functioning (0.92) Role-emotional (1.32) Mental health (0.68) Reported health transition (0.80) MHAQ (1 4, 4 worst health) (0.02) AIMS2 (0 10, 10 worst health) Physical (0.07) Affect (0.06) Symptom (pain) (0.08) Social interaction (0.05) VAS (0 100, 100 worst health) Pain (0.75) Fatigue (0.88) * Adapted from Kvien, et al AIMS2 = Modified Arthritis Impact Measurements Scales; MHAQ = Modified Health Assessment Questionnaire; SE = standard error; SF-36 = Short-form Health Survey; VAS = Visual Analogue Scale 2 New Evidence in Rheumatology January 2009

4 Five-year prospective studies in the UK, Scandinavia, and continental Europe show that in early RA there is a J-shaped curve for physical function as measured using HAQ scores. 5 The explanation for this J-shaped curve is that patients with RA start with considerable disability before treatment is initiated. Symptom-relieving treatments and disease-targeting agents such as non-biologic disease-modifying anti-rheumatic drugs (DMARDs) initially improve synovitis and associated disability. However, disability subsequently rises with increasing joint damage, resulting from a reduction in response to therapy. Using other treatments that have different mechanisms of actions from non-biologic DMARDs may therefore reduce disability and improve patient QoL. Indicators of treatment success in rheumatoid arthritis Defining remission in rheumatoid arthritis Complete or partial control of RA is essential to prevent long-term joint damage. 6 With the development of biologic DMARDs, remission in RA is now more feasible than in the past. Although remission is recognized as the goal of therapy in RA, there is currently no standard definition of remission that can be applied in RA. Unlike the concept of remission in cancer, the definition of remission in RA is complicated by a number of disease factors. 6 RA patients often undergo spontaneous remissions in the early phases of the disease that may only last a few months. In past reports, the time frame for identifying remission varied from two months to two years. Identification of a time frame within the definition of remission is therefore important. Also, because RA involves disregulation of normal immune system cells, remission cannot necessarily be defined as a disease-free state. Finally, the stage of the disease must be considered. Remission is different in patients with early disease as compared with those who have established disease and irreversible damage. Due to the absence of a gold standard measurement, recognition of remission requires multiple measures or indices. Measures of disease activity in rheumatoid arthritis A number of measurement tools of disease activity have been developed in RA. 6 (Table 2) The traditional approach is the American College of Rheumatology (ACR) criteria for remission, which has 90% sensitivity and 69% specificity for complete remission when four criteria are met. When five criteria are met, sensitivity increases to 92% and specificity to 72%. However, the ACR evaluation may be confounded by co-morbidities with similar symptoms, such as fibromyalgia or osteoarthritis. The ACR criteria have limitations in clinical practice, as they require a baseline for comparison. 8 They also are dichotomous in nature and therefore cannot provide results on a continuous scale reflecting actual disease activity. An advance in disease activity assessment was the development of the Disease Activity Score (DAS). 8 The DAS includes a composite score based on tender and swollen joint counts, erythrocyte sedimentation rate (ESR), and patient assessment of global health. This composite measure allows for evaluation of disease activity on a continuous scale. Determining a DAS value requires extended joint examinations for swelling and grading joints for tenderness by the Ritchie index. The transformation of the original DAS to the DAS28, which employs a 28-joint count, was successfully achieved to enable the use of reduced joint counts while eliminating the need to grade tender joints. The DAS28 was found to overestimate the original DAS, as it does not include data related to feet and ankles. 6 The DAS28 represents a disease activity state, while the ACR response criteria represent a means to determine the proportion of patients who respond to a treatment at any time point. 8 The ACR response criteria are relevant to studies, but the DAS is more useful in the practice setting as it can account for multiple outcomes at one point in time. However, the DAS and DAS28 are difficult to calculate given their complex formulas, and do not take into account the evaluator s global assessment or CRP levels. A DAS calculator can be used to make the complex mathematical formulas involved in calculating DAS scores easier. New Evidence in Rheumatology January

5 DAS-derived simplified indices have been developed, including the simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI). 8 These DAS-derived indices are correlated significantly with the DAS28 except for the category of remission, in which SDAI and CDAI are more stringent. The Rheumatoid Arthritis Disease Activity Index (RADAI) is a well-validated scale of patient-reported RA disease activity. 9 The RADAI is comprised of three pain items scored 0 to 10, one stiffness item scored 0 to 6, and a homunculus of painful joints scored 0 to 48. Scoring of the RADAI requires transformation of all items to a scale of 0 to 10 and an arithmetic mean of all five items. A global assessment of disease activity can also be used to obtain data on the patient s assessment of disease severity. Global assessment uses a Likert scale to measure the patient s overall assessment of disease activity. 10 Measures of disability and quality of life in rheumatoid arthritis The original Stanford HAQ was designed as a twentyitem self-administered questionnaire examining eight dimensions of difficulties with the performance of activities of daily living: dressing, getting up, eating, walking, hygiene, grip, reach, and other activities. 7 Raw scores are transformed into separate disability and pain severity indices ranging from 0 to 3 with a low score indicating no difficulties. Modification of the HAQ (MHAQ) is done by reducing the number of items to one item within each dimension of difficulty, with a total of eight questions. The MHAQ has been shown to provide essentially the same information as the longer original HAQ. The SF-36 was developed to measure eight of the most commonly used dimensions in health surveys. 7 It contains 36 items and is scored as eight multiitem scales plus one item measuring a self-evaluated change in health status. The SF-36 is a generic measure, meaning that its concepts are not specific to age, disease, or treatment group. This allows for comparisons of the relative burdens of different diseases and benefits of different treatments. It is suitable for self-administration. The eight multi-item scales include physical functioning (10 items), role limitations due to physical health (4 items), bodily pain (2 items), general health (5 items), vitality/energy/ fatigue (4 items), social functioning (2 items), role limitations due to emotional problems (3 items), mental health (5 items), plus the one-item measure on reported health transition. A Visual Analogue Scale (VAS) is a measurement instrument that tries to quantify a characteristic or attitude ranging across a continuum of values. 11 For example, the amount of pain or fatigue that a patient feels ranges from none to an extreme amount. From the patient s perspective, this spectrum appears continuous without obvious categorization to none, mild, moderate, or severe. Operationally, a VAS is a horizontal line, 100 mm in length, anchored by word descriptors at each end. Patients mark the point on the line that they feel represents the perception of their current state. The VAS score is determined by measuring in millimeters from the left-hand end of the line to the point that the patient marks. The Nottingham Health Profile (NHP) is based on interviews with patients, who are asked to assess how they feel when experiencing various states of ill health. 10 The NHP contains 38 statements that assess subjective distress in six domains: physical mobility (8 items), pain (8 items), sleep (5 items), energy (3 items), social isolation (5 items), and emotional reactions (9 items). The respondent is required to answer yes or no to each statement, and these are weighted empirically in terms of their perceived severity. The scores for each section may range from 0 (no problems or absence of limitations) to 100 (all problems listed are present). A health profile, such as the NHP, provides multiple outcomes that may be useful to clinicians and/or researchers who are attempting to measure the differential effects of a condition or its treatment on various HR-QoL domains. The NHP can be completed in 5 to 10 minutes, and its administrative burden is minimal. Thus, the NHP is suitable for out-patients in clinical practice. The original AIMS questionnaire contained 45 items, grouped into nine scales covering different areas. 7 These scales could be combined to produce overall models of health status with three or five components. The revised AIMS2 contains three additional scales and also includes sections which assess satisfaction with function, attribution of problems to arthritis, and self designation of priority areas of improvement. It contains a total of 78 questions, of which the first 57 items are broken into twelve scales: mobility (5 items), walking and bending (5 items), hand and finger function (5 items), arm function (5 items), selfcare tasks (4 items), household tasks (4 items), social activity (5 items), support from family and friends (5 items), arthritis pain (5 items), work (4 items), level of tension (5 items), and mood (5 items). 4 New Evidence in Rheumatology January 2009

6 One additional item in the AIMS2 questionnaire estimates the overall impact of arthritis, and three items explore co-morbidity. The scales may be combined into a five-component model reflecting the physical dimension (mobility level, walking and bending, hand and finger function, arm function, self-care tasks, household tasks), affect (level of tension, mood), symptoms (pain), social interaction (social activity, support from family and friends), and role (work). Table 2. Measurement tools used to assess disease activity, physical function, and quality of life in patients with RA Criteria Definition Measures of disease activity ACR 6 Modified ACR 6 FDA Guidelines 6 Absence of five out of the following six criteria over a two-month period: Fatigue Joint pain Joint tenderness Swelling of joints or tendon sheaths Morning stiffness ESR <30 mm/h in women or <20 mm/h in men Absence of four out of the last five ACR criteria (i.e., fatigue is not taken into consideration) over a two-month period ACR criteria + radiographic arrest off-therapy over a six-month period DAS x (Ritchie) x SJC lognat (ESR) x GH <1.6* DAS x (TJC) x SJC lognat (ESR) x GH <2.6* CDAI 6 SDAI 6 RADAI 9 Patient Global Evaluation 10 SJC + TJC + PGA (cm) + TJC (cm) 2.8* SJC + TJC + PGA (cm) + TJC (cm) + CRP (mg/dl) 3.3* Three pain items scored 0 10, one stiffness item scored 0 6, and a homunculus of painful joints scored 0 48 Scoring of the RADAI requires transformation of all items to a scale of 0 10 and an arithmetic mean of all five items Likert scale to measure the patient s overall assessment of disease activity Measures of disability and quality of life HAQ 7 MHAQ 7 SF-36 7 VAS 11 NHP 10 AIMS 7 AIMS2 7 Measures difficulties in 20 areas of daily living Raw scores are transformed into separate disability and pain severity indices ranging from 0 3 with a low score indicating no difficulties Reduces number of questions in the HAQ to eight in total Measures physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, mental health, and role limitation due to emotional problems Score ranges from 0 100; low scores indicate poor health Horizontal line, 100 mm in length, anchored by word descriptors at each end Can be used to measure patients perception of pain, fatigue, and other symptoms Assesses physical mobility, pain, sleep, emotional reaction, social isolation, and energy Scores range from 0 100, low scores being negative 45 items grouped into 9 scales covering different areas of disability and quality of life Contains 3 scales and sections added to the AIMS, which assess satisfaction with function, attribution of problems to arthritis, and self designation of priority areas of improvement Contains a total of 78 questions * State of remission ACR = American College of Rheumatology; AIMS = Arthritis Impact Measurements Scales; AIMS2 = Modified Arthritis Impact Measurements Scales; CDAI = Clinical Disease Activity Index, CR = C-reactive protein; DAS = Disease Activity Score; ESR = erythrocyte sedimentation rate; FDA = Food and Drug Administration; GH = global health by visual analogue scale; HAQ = Health Assessment Questionnaire; MHAQ = Modified Health Assessment Questionnaire; NHP = Nottingham Health Profile; PGA = patient global assessment of disease activity; Ritchie = Ritchie articular index; SDAI = simplified Disease Activity Index; SF-36 = Short-form Health Survey; SJC = swollen joint count; TJC = tender joint count; VAS = Visual Analogue Scale New Evidence in Rheumatology January

7 Determination of initial response to rituximab in rheumatoid arthritis As discussed earlier, defining remission or treatment success is complicated by numerous disease factors. 6 However, in order to make decisions about repeating treatment with rituximab, it is important to identify patients that are initially responsive. Table 3 reports the ACR 2008 recommendation cut-off values for disease activity states, based on established clinical outcome indices. 8,12 Table 3. Cut-off values for different disease activity states* Index Score range Disease activity state Remission Low Moderate High SDAI >11 and 26 >26 CDAI >10 and 22 >22 RADAI 0 10 n/a < and 4.9 >4.9 DAS < >3.2 and 5.1 >5.1 * Adapted from Saag, et al. ACR 2008 Recommendations; Aletaha, et al ,12 Median CDAI = Clinical Disease Activity Index; DAS28 = Disease Activity Score in 28 joints; n/a = not applicable; RADAI = Rheumatoid Arthritis Disease Activity Index; SDAI = Simplified Disease Activity Index In the New Evidence interview, Dr. Bykerk suggested that a patient exhibiting at least a 20% improvement in disease activity at approximately 3 4 months may be eligible for re-treatment. Dr. Bykerk noted that the 20% marker is somewhat arbitrary and depends on the outcome measure used. However, any outcome that does not show at least a 20% response suggests that the patient did not respond well enough to justify repeating treatment with the same agent. The 20% marker of disease activity improvement is supported by the ACR definition of response, which is at least a 20% improvement in tender and swollen joint counts and a 20% improvement in three of the five remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. 13 This marker is also supported by the rituximab reimbursement criteria in both the Northwest Territories (NWT) and in Quebec, which define response as being at least a 20% positive change in specified measurement criteria. 14 In the NWT, these criteria include a 20% improvement in the number of tender and swollen joints, plus physician global assessment, plus either patient global assessment or acute phase as measured by erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). In Quebec, these criteria include one of the following: a 20% improvement in the ESR, rheumatoid factor (RF), or HAQ; or return to employment. (Appendix A) In some cases, patients with a constant level of disease activity may continue to experience radiographic progression, even in the absence of an increase in disease activity. 15 There is some evidence to suggest that patients treated with non-biologic DMARDs show improved disease activity, but have a greater increase in x-ray damage scores compared with patients treated early with TNF-Is. Monitoring of radiographic outcomes in addition to typical measures of disease progression is therefore important in patients with RA. 6 New Evidence in Rheumatology January 2009

8 Determining the need for repeat treatment with rituximab Defining and measuring flares in rheumatoid arthritis At approximately 6 12 months after initial treatment with rituximab, patients may experience a flare (an increase in disease activity). 16 According to Dr. Bykerk, there is a lot of variation in time-to-flare after initial treatment. Some patients may experience flares at ten months, while others may see an increase in disease activity as early as five months. According to Smolen, et al., 16 repeat treatment with rituximab should be considered in responders who have considerable residual disease activity or who deteriorate clinically after initial response. Moderate disease activity (DAS28 >3.2, CDAI >10, or SDAI >11) is considered by the authors to be significant residual disease activity. Clinical deterioration has not been formally defined. However, a deterioration in the clinical status, such as an increase in DAS28 of >0.6 or an equivalent change in disease activity, is considered a clinically relevant deterioration. Dr. Bykerk believes that an increase in disease activity of 10% 20% may be used as a reasonable marker for clinically relevant deterioration. Current coverage of rituximab re-treatment in Canada Re-treatment with rituximab therapy is currently approved in many provinces in Canada. 14 In provinces that grant approval, criteria for repeat treatment usually include those patients who have achieved a response followed by a subsequent loss of effect after an interval of no less than six months since the previous dose. Reimbursement criteria by province are outlined in Appendix A. Impact of current rituximab reimbursement criteria Due to stringent reimbursement criteria and, in some provinces, lack of reimbursement for repeat treatment with rituximab in RA, rheumatologists in Canada are often limited in their ability to offer their patients optimal treatment. 2 After an application in Ontario for rituximab at six months, Dr. Bykerk said, an additional six weeks goes by before you get the green light to use it. Once you are authorized to give the drug, you have only one month to administer it. Some patients may experience an increase in disease activity before the six-month mark. For example, a patient experiencing a flare at five months would not have access to repeat treatment with rituximab for more than two months (4 weeks + 6 weeks approval). During this time, the patient may experience further worsening of disease activity, QoL, and joint damage. Figure 1 presents a hypothetical example of two patients: one optimal case and one patient with uncontrolled RA. Rituximab is given every six months, and patients are monitored based on their DAS score. In this case, the DAS score could be replaced with any other measure of disease activity. In the optimal case, the patient begins to flare after six months. If rituximab is immediately available, the patient can be given treatment immediately, allowing for a further reduction in DAS as has been seen with repeated courses of rituximab. 17 With flares occurring approximately every six months, this patient can be re-treated every six months, resulting in a low DAS score. In the fluctuating patient, the initial flare begins at five months. As the rheumatologist would not be able to apply for rituximab until six months and would have to wait an additional six weeks before approval, the patient s DAS score may increase back to initial levels before repeat treatment is given. If, after rituximab treatment, the patient s DAS score were to increase every five months instead of every six months, the result would be a fluctuating response pattern. In this case, the patient s DAS would remain at high levels as a result of a delay in retreatment with rituximab. According to Dr. Bykerk, this delay in receiving rituximab and the six-month cut-off before applications are accepted impair the ability of rheumatologists to offer patients the best individualized care. New Evidence in Rheumatology January

9 Figure 1. Fluctuating versus optimal pattern of disease activity with rituximab treatment Disease Activity Score (DAS) Optimal Fluctuating Time (months) Determining optimal treatment intervals The approximate time interval to re-treatment appears to be between six and twelve months. 3 However, data are lacking in the rituximab re-treatment setting, and the median interval between infusions is still not clear. But, certainly, all patients would not have an optimal treatment interval over six months. For patients who experience flares before six months, a similar fluctuating pattern as was presented in Figure 1 might result. This pattern would prevent the patient from reaching a low disease activity state, especially given the length of time required to receive approval for rituximab. Because of the long delay, some rheumatologists may automatically apply for approval at six months, even if patients have not experienced a flare, so that the drug is available when needed. In Dr. Bykerk s opinion, rheumatologists need to have the flexibility to apply for rituximab as soon as the patient shows any sign of flare. With stringent guidelines that do not take into account individual variations in disease progression, under- or over-treatment may result. Development of a patient assessment tool for early detection of flares The purpose of the proposed assessment tool is to address many of the issues discussed above in the use of rituximab re-treatment for RA. Description of the proposed assessment tool At the ACR/AHRP 2008 rituximab re-treatment advisory board, Dr. Bykerk, along with a group of experts in RA, proposed the development of a patient assessment tool for early detection of flares. The tool was discussed in detail at the advisory board. The first section of the tool could contain a patient education component which would aid in setting patient expectations around repeat treatment with rituximab. This section would also educate patients on how to use the tool to self-monitor their disease activity level and QoL. Instructions on when to call their rheumatologist and an adjustable infusion schedule could be included in the form of a calendar. 8 New Evidence in Rheumatology January 2009

10 The second section of the tool could have a patient tracker that would allow patients to monitor their progress on rituximab over time. (Figure 2) The tracker would contain multiple indicators of disease progression and measures of QoL, with a time period to denote recording frequency. Dr. Bykerk identified the following measures to include in the tool: disease progression indicators such as the number of swollen and tender joints and DAS; lab indicators such as ESR and CRP; and QoL measures such as HAQ, fatigue, pain, and productivity VAS. Patients would record either a numeric or categorical score to indicate improvements or worsening of measurement indicators over time. The first step in using the tool would be to collect baseline measures at initial treatment with rituximab (time 0) to be used for comparison. At approximately three to four months, the patient would be asked to come in for assessment of initial response to rituximab. As discussed earlier, at least a 20% improvement from baseline in disease activity measures should be obtained for a patient to be considered eligible for re-treatment. 13 Some consideration for repeat treatment in patients with significant residual disease activity should also be given. 16 After the assessment of initial response to rituximab, patients would be asked to monitor their symptoms according to a number of disease activity criteria. The measures considered for inclusion in the tool need to be examined for sensitivity to change in disease activity. If patients experienced at least a 10% 20% worsening of scores over a period of two sequential months, they would be asked to have a blood test to measure ESR and CRP levels. If lab results indicated inflammation and disease progression, the patient would be asked to come in for a joint count to confirm the presence of a flare. Advantages of the proposed assessment tool The proposed tool may aid in solving many of the re-treatment issues identified at the ACR/ARHP 2008 advisory board. The ultimate benefit of such a tool would be to standardize decisions in re-treatment, while taking into consideration individual differences in disease progression. Patients exhibiting an early increase in disease activity could then benefit from earlier repeat treatment with rituximab, preventing the fluctuating pattern shown in Figure 1. In addition, the tool would aid in the creation of a standardized definition of clinical deterioration through the use of multiple indicators. The tool s educational component could increase patients understanding of their condition and allow them to selfmonitor their symptoms, giving them more control over the management of their disease. The tool would also help patients to develop realistic expectations for repeat treatment, which will allow them to create achievable goals. Figure 2. Example of a potential patient tracking tool Possible Criteria Tender/swollen joint ESR HAQ CRP Global scale of productivity Fatigue VAS Pain VAS Productivity VAS Morning stiffness RADAI Other criteria Month/Increase or decrease from previous month 0 3 +/- 4 +/- 5 +/- 6 +/- 7 +/- Continued CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; HAQ = Health Assessment Questionnaire; RADAI = Rheumatoid Arthritis Disease Activity Index; VAS = Visual Analogue Scale New Evidence in Rheumatology January

11 The proposed assessment tool would also be valuable for treating patients in remote areas who do not have immediate access to a rheumatologist. Because the tool allows patients to self-monitor disease activity, RA patients in Canada s northern communities where tuberculosis (TB) is a problem may be able to use rituximab, a drug with a low risk of TB, for repeat treatment. Such a tool could also greatly reduce the time that rheumatologists and other members of the health care team spend seeing patients who are not experiencing flares. The tool could help to develop a standard protocol to aid in scheduling physician visits and infusions. As the tool would be used over time and might include many repeat treatments, it could help to establish optimal treatment intervals for individual patients and to estimate time intervals for repeat treatment. Next steps in the development of the patient assessment tool The next step in the development of the assessment tool is to create a first draft to be used in a pilot study. Disease activity and QoL measures would be tested for sensitivity to change and appropriateness for inclusion in the tool. The tool could then be retrofitted to longitudinal data from previous studies, such as the REFLEX 17 data set, to measure the tool s performance. If this tool is shown to effectively detect early flares in a rituximab responder, it may be appropriate to apply the results of the tool to determine when patients need re-treatment. Potentially, such a tool could be used by ministries of health as a way to establish reimbursement criteria for repeat treatment. Summarizing the advantages of the proposed patient assessment tool The October 2008 rituximab advisory board discussed common issues concerning the repeat use of rituximab in the treatment of rheumatoid arthritis. The setting of realistic patient expectations was a key area of discussion. Board members felt that patient education was needed to increase understanding of what to expect from rituximab treatment, and that the proposed assessment tool could include an educational component to fulfil this purpose. The tool would also allow patients to self-monitor their disease activity and quality of life, giving them more control over their condition. Logistical issues discussed during the advisory board included scheduling around obtaining and using rituximab, establishing frequency and timing of patient appointments, and administering infusions. The proposed tool would establish a standardized protocol for the use of rituximab in rheumatoid arthritis. Monitoring frequency and standardized outcome criteria would be clearly outlined in the tracking tool. In addition, the inclusion of a calendar would aid patients and their healthcare team to keep track of when to order and administer rituximab infusions, and the frequency and timing of physician appointments. Unnecessary appointments would be minimized through patient self-monitoring, allowing the healthcare team to focus on patients more likely to experience flares. Individualizing treatment to minimize adverse effects and ensure the best patient care was the overall key message from the advisory board meeting. Current Canadian reimbursement guidelines do not take into account individual variations in the time-to-flare. In addition, time to approval of rituximab for re-treatment is generally lengthy. As a result, patients may not be receiving rituximab at the optimal time and interval to effectively reduce disease activity. The goal of the proposed patient assessment tool is to optimize patient care through early detection of flares. If proven to perform effectively, this tool may be a good alternative to current reimbursement criteria for acquiring rituximab for repeat treatment in rheumatoid arthritis. 10 New Evidence in Rheumatology January 2009

12 Appendix A. Provincial coverage of rituximab in Canada* Province British Columbia New Brunswick Newfoundland and Labrador Northwest Territories Alberta Manitoba Nova Scotia Nunavut Ontario Prince Edward Island Coverage Eligible for coverage through the Special Authority Program for the treatment of RA with the following criteria: For the treatment, in combination with MTX, of patients with severely active RA who have failed to respond to an adequate trial of two TNF-Is (adalimumab or infliximab, and etanercept) or have contraindications to other TNF-Is. Rituximab should not be used concomitantly with other TNF-Is. Re-treatment is considered for 1 course per year. Listed as exception status benefits under the New Brunswick Prescription Drug Programs. Specific criteria: For adults with severely active RA who have failed to respond to an adequate trial with an anti-tnf agent. Rituximab cannot be used concomitantly with anti-tnf agents. Re-treatment considered for patients who have achieved a response followed by a subsequent loss of effect, after an interval of a no less than 6 months from the previous dose. For the treatment of adult patients with severely active RA who have failed to respond to an adequate trial with a TNF-I: Rituxmab is not reimbursed concomitantly with TNF-Is. Re-treatment considered for patients who have achieved a response followed by a subsequent loss of effect, after an interval of a no less than 6 months from the previous dose. Covered by the NIHB as a Limited Use Benefit (prior approval required) when prescribed by a rheumatologist for treatment of adult patients with severely active RA who have failed to respond to a trial of a TNF-I. Treatment should be combined with MTX and should not be used in combination with TNF-Is. Re-treatment for coverage beyond 24 weeks, the patient must meet all the following criteria: Initially prescribed by a rheumatologist. Patient has been assessed after weeks of therapy and meets the response criteria of: >20% reduction in number of tender and swollen joints PLUS >20% improvement in physician global assessment scale PLUS EITHER >20% improvement in the patient global assessment scale OR >20% reduction in the acute phase as measured by ESR or CRP Rituximab is not currently on the Alberta Health and Wellness Drug Benefit List (currently under review). Rituximab is not currently listed on the Manitoba Pharmacare Formulary. When a drug is not listed in the Formulary, a request for Exception Drug Status coverage will be considered under Part III of the drug benefits list based on each individual s specific circumstance. Rituximab is listed as exception status benefits under the Nova Scotia Pharmacare Programs. Specific criteria: For adults with severely active RA who have failed to respond to an adequate trial with an anti-tnf agent. Cannot be used concomitantly with TNF-Is. Re-treatment considered for patients who have achieved a response followed by a subsequent loss of effect, after an interval of a no less than 6 months from the previous dose. Rituximab is not currently on the Health Benefits Program s Drug Benefit List. Drugs not included in the Drug Benefit List may be covered under exceptional circumstances. Considered for reimbursement through the Individual Clinical Review mechanism with the following revised criteria: For the treatment of adult patients with severely active RA who have failed to respond to an adequate trial of one TNF-I. Rituximab should not be used concomitantly with other TNF-Is. The patients should have also failed adequate trials of DMARDs or were intolerant to them. The patient should be rheumatoid factor positive OR have radiographic evidence of rheumatoid joint damage; and have at least 5 swollen joints. The approved dosing for rituximab is 1,000 mg followed two weeks later by the second 1,000 mg dose. Re-treatment considered for patients who have achieved a response followed by a subsequent loss of effect, after an interval of no less than 6 months since the previous dose. Rituximab is not currently listed on the PEI Drug Programs Formulary. To request coverage of medications not listed on the Formulary, the prescribing physician must fill out and send an Exceptional Drug Request Form to PEI Drug Cost Assistance Programs. New Evidence in Rheumatology January

13 Appendix A. Provincial coverage of rituximab in Canada* Province Coverage Considered for reimbursement through La Liste de médicaments du Régime général d assurance médicaments (RGAM) mechanism. Quebec Saskatchewan Yukon Before the start of treatment, patient must have 8 joints or more with active synovitis, one joint or more with radiological erosion, and one of the following 4 elements: 1. A positive rheumatoid factor 2. A score above 1 on the HAQ health assessment questionnaire 3. An elevation of the C-reactive protein value 4. An increase in the sedimentation rate AND The disease must still be active despite treatment for 4 months or longer with infliximab, or 3 months or more with etanercept or adalimumab, except in cases of serious intolerance or contraindications. The initial authorization is given for a treatment consisting of 2 perfusions of rituximab of 1,000 mg each. Re-treatment must provide the data demonstrating a response to treatment 3 months after the last injection, followed by a loss of its efficacy. Response to treatment is defined as a reduction of 20% or more of the number of joints with active synovitis and one of the 4 following elements: 1. A reduction of 20% or more of the value of the C-reactive protein 2. A reduction of 20% or more of the sedimentation rate 3. A reduction of 0.20 of the HAQ score 4. Return to employment Each subsequent treatment is authorized after an interval of at least 6 months since the last perfusion of rituximab. Each authorization is given for a treatment consisting of 2 perfusions of rituximab of 1,000 mg each. Rituximab is covered by Saskatchewan Health through Exception Status Drug program according to the following criteria: For the treatment of severely active RA in combination with methotrexate in adults who have failed to respond to an adequate trial of a TNF-I. Rituximab should not be used concomitantly with anti-tnf agents. Re-treatment with rituximab is not discussed. Rituximab is covered by Yukon Pharmacare according to the following criteria: For severe RA, when used in combination with MTX and when failure of TNF-I trial. Coverage is for 6 months. Re-treatment considered for patients who have achieved a response, followed by loss of effect after an interval of no less than 6 months since dose. * Adapted from Arthritis Consumer Experts 14 CRP = C-reactive protein; DMARD = disease modifying anti-rheumatic drug; ESR = erythrocyte sedimentation rate; HAQ = Health Assessment Questionnaire; MTX = methotrexate; RA = rheumatoid arthritis; TNF = tumour necrosis factor; TNF-I = tumour necrosis factor inhibitor References: 1. Palylyk-Colwell E, McGahan L. Rituximab for rheumatoid arthritis. Issues Emerg Health Technol 2006;89: Edworthy S, Zummer M, Garner S, et al. Smoldering rheumatoid arthritis: is the Canadian healthcare system neglecting a significant disease population? J Rheumatol 2008;35: Jois RN, Masding A, Somerville M, et al. Rituximab therapy in patients with resistant rheumatoid arthritis: real-life experience. Rheumatology 2007;46(6): PR RITUXAN Product monograph. Hoffmann-La Roche Ltd. September 25, Pollard L, Choy EH, Scott DL. The consequences of rheumatoid arthritis: quality of life measures in the individual patient. Clin Exp Rheumatol 2005;23(5 Suppl 39):S43 S Valesini G, Di Franco M, Spinelli FR, Scrivo R. Induction of remission in rheumatoid arthritis: criteria and opportunities. Rheumatol Int 2008;29(2): Kvien TK, Kaasa S, Smedstad LM. Performance of the Norwegian SF-36 Health Survey in patients with rheumatoid arthritis. II. A comparison of the SF-36 with disease-specific measures. J Clin Epidemiol 1998;51(11): Aletaha J, Smolen D. The Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) to monitor patients in standard clinical care. Best Pract Res Clin Rheumatol 2007;21(4): Stucki G, Liang MH, Stucki S, et al. A self-administered rheumatoid arthritis disease activity index (RADAI) for epidemiologic research. Arth Rheum 1995;38: Uutela T, Hakala M, Kautiainen H. Validity of the Nottingham Health Profile in a Finnish out-patient population with rheumatoid arthritis. Rheumatology 2003;42(7): Wewers ME, Lowe NK. A critical review of visual analogue scales in the measurement of clinical phenomenon. Res Nurs Health 1991;14(1): Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59(6): Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38(6): Arthritis Consumer Experts. Report card on provincial formulary reimbursement listings for biologic response modifiers. Accessed December, Haraoui B. What constitutes nonresponse in rheumatoid arthritis? Rheumatoid Arthritis National Grand Rounds 2008;4(2). 16. Smolen JS, Keystone EC, Emery P, et al. Consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2007;66(2): Keystone EC, Fleischmann RM, Emery P, et al. Efficacy and safety of repeat treatment courses of rituximab (RTX) in RA patients (pts) with inadequate response (IR) to tumor necrosis factor (TNF) inhibitors: long-term experience from the REFLEX study. Program and abstracts of the 2008 American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) Scientific Meeting, October 24 29, 2008, San Francisco, CA: Abstract New Evidence in Rheumatology January 2009

14 PUBLICATIONS MAIL AGREEMENT NO RETURN UNDELIVERABLE CANADIAN ADDRESSES TO NEW EVIDENCE 4133 DUNDAS ST. WEST TORONTO ON M8X 1X2 New Evidence in Rheumatology is an independent medical news reporting service providing educational updates on current medical events. Views expressed are those of the participants and do not necessarily reflect those of the publisher or the sponsor. Support for development and distribution of this report was provided by Roche Rheumatology through an unrestricted grant without conditions and under written agreement that ensures independence. Any therapies mentioned in this report should be used in accordance with the recognized prescribing information. No claims or endorsements are made for any products, uses, or doses presently under investigation. Information provided herein is not intended to serve as the sole basis for individual care. Our objective is to facilitate understanding of current trends in rheumatology for physicians and allied healthcare providers.