Johannes W. G. Jacobs

The Effectiveness of Early Treatment with “Second-Line” Antirheumatic Drugs: A Randomized, Controlled Trial

In recent years, therapeutic strategies for patients with rheumatoid arthritis have been discussed in detail [1-8]. Traditional therapy, usually referred to as the pyramid model, begins with nonsteroidal anti-inflammatory drugs (NSAIDs). If these are insufficiently effective, they are later replaced or supplemented with second-line antirheumatic drugs, which are distinguished from NSAIDs primarily by their assumed disease-modifying potential and delayed onset of action. These second-line drugs are also referred to as slow-acting antirheumatic drugs (SAARDs) or disease-modifying antirheumatic drugs (DMARDs). Traditionally, the SAARDs of first choice have been hydroxychloroquine or intramuscular gold followed by D-penicillamine, methotrexate, or azathioprine. The traditional therapeutic pyramid is based on the principle of primum non nocere: Because of their potential toxicity, SAARDs should only be given when milder therapies have failed. Recently, the beneficial effects of the pyramid strategy have been questioned because the long-term outcome of rheumatoid arthritis continues to be disappointing. Patients with rheumatoid arthritis have increased mortality [9, 10], and their quality of life is seriously affected by functional impairment and loss of employment [11, 12]. The pyramid model might be undesirable because administering SAARDs only after milder regimens prove to be insufficiently effective delays the suppression of inflammation. It is preferable that the disease process be controlled as soon as possible, because radiologic abnormalities appear in the joints early in the course of the disease [13, 14] and are related to the extent of inflammation [15, 16]. Toxicity indices for NSAIDs and most SAARDs have recently been shown to be similar; thus, exposure of patients to possible adverse reactions is probably not in itself a reason to withhold treatment with SAARDs [17]. However, the ability of SAARDs to modify the course of disease and prevent radiologic damage is often questioned [18, 19]. The poor long-term outcome of rheumatoid arthritis might be caused not by a delay in effective treatment but by the low disease-modifying power of both first- and second-line drugs. The short courses of SAARDs (short because of adverse reactions or impatience with a delay in effect) might also play a role [20, 21]. Combinations of SAARDs have not been shown to be superior to single drugs [21, 22]. Current clinical practice is shifting toward the earlier introduction of second-line treatment for rheumatoid arthritis, but thus far no clinical trials have shown this strategy to be beneficial. We investigated the consequences of ignoring the treatment pyramid for patients with recent-onset rheumatoid arthritis. In this report, we describe the first-year results of a randomized clinical trial in which the delayed and the immediate introduction of SAARDs were compared. Effectiveness was measured by disease activity and progression of radiologic abnormalities. The various SAARDs are considered as a single group in this report; comparisons among the second-line therapies will be reported in detail later. Methods Patients As of January 1990, all patients with recent-onset rheumatoid arthritis (diagnosed according to the 1987 American College of Rheumatology criteria [[23]] from six rheumatologic centers in the region of Utrecht, the Netherlands, were asked to participate in a randomized, prospective clinical trial. Disease duration had to have been less than 1 year, and most patients were enrolled shortly after diagnosis. The following exclusion criteria were applied: 1) age younger than 17 years, 2) comorbid conditions that might interfere with one of the therapeutic strategies, 3) previous or current treatment with any SAARDs, glucocorticosteroids, or cytotoxic or immunosuppressive therapy, 4) the possibility of pregnancy or breast feeding, and 5) psychiatric or mental disturbances that would make adherence to the study protocol unlikely. All patients gave informed consent before study entry and were told that the study was intended to compare the unsure outcome of treatment with NSAIDs alone with that of treatment with NSAIDs and a SAARD for rheumatoid arthritis at an early stage. The study design was approved by the ethical committees of all participating hospitals. The baseline characteristics of patients who were eligible for the study but who objected to randomization were compared with those of randomly assigned patients to determine whether any selection bias had occurred. Treatment Patients entering the study were randomly assigned to one of two therapeutic groups. All randomization procedures were done by drawing sealed envelopes from blocks of 100 with equal numbers of patients for each of the four treatments per hospital; the person doing the procedures was blinded to treatment assignments. This method was used because eligible patients were not distributed equally among the centers. The assigned therapeutic strategy was continued for at least 1 year. In the non-SAARD group, patients began receiving NSAID therapy, the dose and type of which could be modified at any time. For this group, initiation of SAARD treatment during the study was regarded as discontinuation of the therapeutic strategy. In the SAARD group, patients were randomly assigned (by persons blinded to treatment assignments) to treatment with one of the following SAARDs: hydroxychloroquine (400 mg/d), intramuscular gold (aurothioglucose, 50 mg/wk), or oral methotrexate (7.5 to 15 mg/wk). Therapy with the initial SAARD was continued for 12 months unless adverse reactions necessitated discontinuation; if this occurred, another SAARD was given. Hydroxychloroquine was followed by auranofin (6 to 9 mg/d); intramuscular gold was followed by D-penicillamine (500 to 750 mg/d); and methotrexate was followed by sulfasalazine (2000 to 3000 mg/d). Discontinuation of therapy with the second SAARD was regarded as discontinuation of the therapeutic strategy. Use of NSAIDs was allowed in the SAARD group; as in the non-SAARD group, the dose and type could be changed at any time. Patients were assigned to the non-SAARD group and the SAARD group in a ratio of 1:3, and power calculations for the primary end point disability ( equals 0.05; equals 0.20; difference to be detected, 25%) indicated that group sizes of 40 and 120, respectively, would be sufficient. The ratio of 1:3 was chosen to enable later comparisons of results within the SAARD group, which were thought to be similar. The use of analgesics was allowed in both groups; the use of oral glucocorticosteroids was avoided if possible; and intraarticular injections were not allowed within 2 months of a scheduled visit. Criteria for discontinuation or dose adjustment of a SAARD because of adverse reactions were described in detail in the study protocol. Discontinuation of any treatment because of sustained disease activity was done only if the patient and the attending physician (who had to discuss the patient with a colleague) judged it to be unavoidable. Primary End Points Assessments were done at the start of the trial and were repeated every 3 months. Clinical variables were assessed by the same physician or research nurse for each patient on each occasion. Primary end points were functional disability, pain, joint score, erythrocyte sedimentation rate, and radiologic abnormalities [24]. Radiologic abnormalities and erythrocyte sedimentation rate were determined by persons blinded to treatment assignments; functional disability and pain were self-assessed scores; and determination of the joint score was not blinded to treatment. Functional disability was assessed using a validated Dutch version of the Health Assessment Questionnaire Disability Score [25-27]. The questionnaire scores range from 0 to 3; 0 is the best score (no problems), and 3 is the worst. Pain was measured on two horizontal visual analog scales of 100 mm; the mean of the scores for pain during the night and pain during the morning was calculated. The joint score according to Thompson and colleagues [28, 29] assessed the simultaneous presence of joint tenderness and swelling in a selection of joints weighed for joint size (range, 0 to 534) [28, 29]. Erythrocyte sedimentation rate (mm/h) was measured using Westergren method. Radiography of hands and feet was done at the start of the study and at 12 months. A modified version of the method of Sharp and coworkers [30, 31] was used to score radiologic abnormalities. According to this method, erosions and joint space narrowing in hand and foot joints are scored and added together to obtain a total radiologic damage score (range, 0 to 448). All radiographs were evaluated by two investigators who were blinded to treatment assignments. The scores of the first investigator were used in the analyses, and the scores of the second investigator were used to validate the scores of the first. Correlation between the two sets of scores was satisfactory (Spearman correlation coefficients for scores at baseline and at 12 months were 0.84 for both); the second investigator was found to have given lower scores (means at baseline were 4.2 and 3.4, respectively; means at 12 months were 11.2 and 9.7, respectively). Therefore, in individual cases, differences in total scores of 25% or more were discussed until an agreement was reached on the appropriate score. That score was then used in the analyses. Additional Assessments Secondary end points were grip strength (mean of three measurements of each hand with a vigorimeter [Martin, Tuttlingen, Germany] in kPa), duration of morning stiffness (maximum, 720 min), and general well-being (horizontal visual analog scale of 100 mm). Additional laboratory variables were serum level of C-reactive protein (mg/L), hemoglobin concentration (mmol/L), and platelet count (times 109/L). Rheumatoid factor status was determined to be positive or negative, as indicated by either the Latex

Women, men, and rheumatoid arthritis: Analyses of disease activity, disease characteristics, and treatments in the QUEST-RA Study

IntroductionGender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA).MethodsThe cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents.ResultsWomen had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but the statistical significance was marginal. Similar proportions of females and males were taking different therapies.ConclusionsIn this large multinational cohort, RA disease activity measures appear to be worse in women than in men. However, most of the gender differences in RA disease activity may originate from the measures of disease activity rather than from RA disease activity itself.

Low-Dose Prednisone Inclusion in a Methotrexate-Based, Tight Control Strategy for Early Rheumatoid Arthritis: A Randomized Trial

BACKGROUND Treatment strategies for tight control of early rheumatoid arthritis (RA) are highly effective but can be improved. OBJECTIVE To investigate whether adding prednisone, 10 mg/d, at the start of a methotrexate (MTX)-based treatment strategy for tight control in early RA increases its effectiveness. DESIGN A 2-year, prospective, randomized, placebo-controlled, double-blind, multicenter trial (CAMERA-II [Computer Assisted Management in Early Rheumatoid Arthritis trial-II]). (International Standard Randomised Controlled Trial Number: ISRCTN 70365169) SETTING 7 hospitals in the Netherlands. PATIENTS 236 patients with early RA (duration <1 year). INTERVENTION Patients were randomly assigned to an MTX-based, tight control strategy starting with either MTX and prednisone or MTX and placebo. Methotrexate treatment was tailored to the individual patient at monthly visits on the basis of predefined response criteria aiming for remission. MEASUREMENTS The primary outcome was radiographic erosive joint damage after 2 years. Secondary outcomes included response criteria, remission, and the need to add cyclosporine or a biologic agent to the treatment. RESULTS Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group. LIMITATION A tight control strategy for RA implies monthly visits to an outpatient clinic, which is not always feasible. CONCLUSION Inclusion of low-dose prednisone in an MTX-based treatment strategy for tight control in early RA improves patient outcomes. PRIMARY FUNDING SOURCE Catharijne Foundation.

Pain coping and social support as predictors of long-term functional disability and pain in early rheumatoid arthritis

Pain-related avoidance factors and social resources, as assessed by pain coping and social support, are supposed to have lasting effects on functional disability and pain in chronic pain disorders. As a follow-up to a prospective study demonstrating short-term effects after one year (Behaviour Research and Therapy, 36, 179-193, 1998), the role of pain coping and social support at the time of diagnosis was investigated in relationship to the long-term course of functional disability and pain after three and five years in 78 patients with rheumatoid arthritis (RA), taking into account personality characteristics of neuroticism and extraversion, clinical status and use of medication. In line with findings at the one-year follow-up, results showed that more passive pain coping predicted functional disability at the three-year, but not the five-year follow-up. In addition, low levels of social support at the time of diagnosis consistently predicted both functional disability and pain at the three and five-year follow-ups. Results indicate that pain coping and social support, assessed very early in the disease process, can affect long-term functional disability and pain in RA, and suggest that early interventions focusing on pain-related avoidance factors and social resources for patients at risk may beneficially influence long-term outcomes in RA.

The course of radiologic damage during the first six years of rheumatoid arthritis.

OBJECTIVE To describe the radiologic course in a large cohort of patients with early rheumatoid arthritis (RA) and to analyze individual components of damage. METHODS Five hundred two patients with recent-onset RA (disease duration <1 year) underwent annual radiologic assessment for a maximum of 6 years in this longitudinal prospective study. The study was designed to investigate the efficacy of 3 different therapeutic strategies. For the assessment of radiologic damage, radiographs of the hands and feet were scored according to the modified Sharp/van der Heijde method (SHS; range 0-448). A mean of 2.9 (range 1-7) radiographs was read per patient. RESULTS Stable rates of progression of the SHS, erosion score, and narrowing score were found over the course of RA: the mean rates were 8.6, 5.4, and 3.2 modified Sharp units per year, respectively. The rate of progression of newly (not previously) damaged joints declined, and the rate of progression of already damaged joints (which became more damaged) increased during followup, leading to an equal contribution to progression of the SHS at 5 years. The joints of the feet, especially the fifth metatarsophalangeal joint, generally became eroded earlier and more of them became eroded compared with the joints of the hands. CONCLUSION Radiologic damage progresses at a constant rate. In advanced disease, monitoring the progression of previously existing damage is as important as assessing new abnormalities in previously undamaged joints. Radiographs of the feet should be included in assessments of radiologic damage that are used in clinical intervention trials and daily practice.

Evaluation and management of endocrine dysfunction in fibromyalgia.

Fibromyalgia-like symptoms such as muscle pain and tenderness, exhaustion, reduced exercise capacity, and cold intolerance, resemble symptoms associated with endocrine dysfunction like hypothyroidism, and adrenal or growth hormone insufficiency. To investigate the potential of management of endocrine abnormalities for relieve of symptoms of patients with fibromyalgia, we reviewed experimental and clinical studies of endocrine functioning and endocrine treatment. Serum GH, androgen, and 24-hour urinary cortisol levels of patients with fibromyalgia tend to be in the lower part of the normal range, while serum levels of thyroid hormone, female sex hormones, prolactin, and melatonin are normal. With exception of GH, these conclusions are based on studies in small samples. With respect to dynamic responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis, the dexamethasone suppression test and stimulation with ACTH show normal results, while patients show marked ACTH hypersecretion in response to severe acute stressors, perhaps indicative of chronic CRH hyposecretion. This finding and slightly altered responsiveness of growth hormone, thyroid hormone, and prolactin in pharmacologic stimulation tests suggest a central rather than peripheral origin of endocrine deviations. Because hormone level deviations were not severe, occurred in subgroups of patients only, and few controlled clinical trials were performed, there is--unless future research shows otherwise--little support for hormone supplementation as a general therapy in the common patient with fibromyalgia. In patients with clinically overt hormone deficiency, hormonal supplementation is an option. In patients with hormone levels that are in the lower part of the normal range, interventions aimed at pain, fatigue, sleep or mood disturbance, and physical deconditioning may indirectly improve endocrine functioning.

Current view of glucocorticoid co-therapy with DMARDs in rheumatoid arthritis

Glucocorticoids are widely used anti-inflammatory and immunosuppressive drugs for rheumatoid arthritis (RA). The disease-modifying potential of low to medium doses of glucocorticoids has been reconfirmed in the past decade, and co-administration of DMARDs and glucocorticoids has become standard in many treatment protocols, especially those for early disease stages but also for long-standing RA. The glucocorticoid regimens used range from continuous low doses to intermittent high doses. Studies of the rationale for and clinical use of glucocorticoids as co-therapy with DMARDs in RA have shown that this approach has a place in modern (tight control) treatment strategies, and that glucocorticoid co-therapy has disease-modifying effects during the first 2 years of treatment in patients with early RA. Furthermore, medium and high doses of glucocorticoids are useful for bridging the interval between initiation of DMARDs and onset of their therapeutic effect. Intra-articular glucocorticoids give good local control and have been used in tight control strategies. New glucocorticoid compounds are becoming available for clinical use that might have an enhanced risk:benefit ratio. Better monitoring of glucocorticoid use will also improve this ratio, and help to allay both patient and rheumatologist concerns about treatment-related adverse effects.

Corticosteroid pulse therapy in active rheumatoid arthritis

The infusion of high doses of corticosteroids (corticosteroid pulse therapy, CPT) is used to treat refractory rheumatoid arthritis (RA). In the first part of this article, literature on the efficacy of CPT is reviewed, and different CPT regimens (high-dose, low-dose, oral CPT) are compared. Several CPT regimens are beneficial in RA, the clinical effect lasting 4 to 10 weeks. Only high-dose CPT (1,000 mg methylprednisolone intravenously) has been shown to bridge the gap between the start and the effect (lag time) of a disease-modifying antirheumatic drug initiated at the same time. A retrospective study on the incidence of short-term and long-term side effects of CPT in 50 patients with RA who received a total of 78 pulse regimens is described in the second part. Side effects occurred frequently, but in most cases they were mild. The possible relationship between CPT and osteonecrosis of the femoral head is discussed. It is concluded that CPT is beneficial in RA. A substantial number of patients suffer side effects of varying severity.

Stress-vulnerability factors as long-term predictors of disease activity in early rheumatoid arthritis.

OBJECTIVE Stress-vulnerability factors were studied for their ability to predict long-term disease activity in early rheumatoid arthritis. METHODS In a prospective study involving 78 recently diagnosed rheumatoid arthritis (RA) patients, the role of personality characteristics (neuroticism, extraversion), physical and psychological stressors (chronic, disease-related stressors of functional disability, pain, disease impact on daily life, as well as major life events), coping and social support at the time of diagnosis was examined to predict changes in clinical indicators of disease activity 1, 3 and 5 years later. RESULTS While stress-vulnerability factors failed to predict disease activity at the 1-year follow-up, disease activity at the 3- and 5-year follow-ups was predicted by coping and social support at the time of diagnosis, after adjusting for disease activity at first assessment, other biomedical and psychosocial factors and use of medication. Low levels of social support predicted increased disease activity at the 3-year follow-up, and high avoidance coping predicted increased disease activity at the 3- and 5-year follow-ups. CONCLUSION Findings indicate the potential prognostic value of avoidance coping and social support for the long-term course of disease activity in early RA and suggest that the effects of these vulnerability factors predominantly operate in the long term.

Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early) : a multicentre, randomised, double-blind, double-dummy, strategy trial

BACKGROUND For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines. METHODS We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137. FINDINGS Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72-78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59-2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48-2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00-1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01-1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study. INTERPRETATION For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards. FUNDING Roche Nederland BV.