Addressing the safety of anakinra in patients with rheumatoid arthritis

Anakinra (Kineret; Amgen Inc., Thousand Oaks, CA) is the first and only recombinant human interleukin-1 receptor antagonist available for therapeutic use. It has been approved by the US Food and Drug Administration and the European Commission for the treatment of patients with rheumatoid arthritis (RA). Anakinra, as an anti-rheumatic therapy, has been assessed in five placebo-controlled clinical trials, either alone or in combination with methotrexate. These trials have shown anakinra to be efficacious and well tolerated by most patients, with the most frequently reported adverse events being mild-to-moderate injection-site reactions that generally resolved rapidly. One of these trials was a large, prospective safety study, which included typical RA patients with a wide variety of co-morbid conditions and receiving concomitant medications. This confirmed that anakinra is a well-tolerated treatment in an RA population representative of that seen by the practising rheumatologist.     

Clinical and radiological effects of anakinra in patients with rheumatoid arthritis

Interleukin-1 (IL-1) is a proinflammatory cytokine that plays a pivotal role in the pathophysiology of rheumatoid arthritis (RA). Inhibiting the activities of IL-1 at the receptor level with the recombinant human IL-1 receptor antagonist anakinra (Kineret; Amgen Inc., Thousand Oaks, CA) is a new therapeutic option for the management of patients with RA. Randomized, placebo-controlled trials have demonstrated that anakinra, alone and in combination with methotrexate, improves the signs and symptoms of RA. Anakinra also produces improvements in patient functionality and health-related quality of life, as measured by the Health Assessment Questionnaire and the Nottingham Health Profile, and reduces the number of productivity days missed due to illness. Furthermore, an initial study indicates that anakinra retards the progression of radiographic joint damage. Such clinical findings suggest that anakinra is an important addition to the rheumatology treatment armamentarium.     

Interleukin 1 receptor antagonist anakinra improves functional status in patients with rheumatoid arthritis

OBJECTIVE: This study evaluated the benefit of anakinra, a human recombinant form of interleukin 1 receptor antagonist, on the functional status of patients with active rheumatoid arthritis (RA) despite taking maximally tolerated doses of methotrexate (MTX). METHODS: Patients (n = 419) were randomized to receive, in addition to MTX (15 to 25 mg/wk), placebo or anakinra doses of 0.04, 0.1, 0.4, 1, or 2 mg/kg once daily for 24 weeks. Functional status measured on 8 scales (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities) was evaluated at baseline and every 4 weeks with the Health Assessment Questionnaire (HAQ). A weighted sum of the scale scores is the HAQ disability index (HAQ-DI). Primary analysis of the HAQ-DI was based on an omnibus test for a positive dose-response relationship between anakinra treatment and change in HAQ-DI from baseline to week 24. RESULTS: Patients receiving anakinra experienced rapid and sizeable improvements in their HAQ-DI scores in a dose-related fashion. For patients receiving either of the 2 highest doses of anakinra, improvements in the HAQ-DI occurred by week 4 that were of a magnitude considered clinically important and statistically significantly superior to placebo. CONCLUSION: In patients with persistence of RA despite MTX therapy, treatment with anakinra results in a rapid improvement in functional status as measured by the HAQ-DI.     

Safety of exercise in patients with rheumatoid arthritis

PURPOSE OF REVIEW: Patients with rheumatoid arthritis benefit from long-term moderate or high-intensity exercises. Moderate or high-intensity exercises were found to improve aerobic capacity, muscle strength, functional ability, and psychological well-being, and slow the age-related and sex-related decrease in bone mineral density of the hip. Despite these positive findings, there is also concern about its risks. Studies on the effects of exercise on disease activity and joint damage are reviewed. RECENT FINDINGS: Studies on the effects of moderate or high-intensity exercise in rheumatoid arthritis demonstrate either decreased or stable disease activity. From the few available studies that address exercise and radiologic progression of the small joints, results indicate that exercises are safe for the joints of hands and feet. However, a recent study suggests caution in prescribing long-term high-intensity weight-bearing exercises to patients who have significant radiologic damage of large joints, as some patients might develop additional damage. SUMMARY: Moderate or high-intensity weight-bearing exercises are safe with respect to disease activity and radiologic damage of the hands and feet. In the absence of sufficient data on exercise and radiologic progression of the large joints, patients with significant radiologic damage of the large joints should not be encouraged to participate in moderate to high-intensity weight-bearing exercise unless individualized to protect affected joints. A broader dissemination of the effectiveness and safety of moderate and high-intensity exercise for patients with rheumatoid arthritis is needed among rheumatologists, physical therapists, and patients.     

Safety profile of tacrolimus in patients with rheumatoid arthritis

We assessed the safety of tacrolimus therapy for rheumatoid arthritis. Forty-two patients who started tacrolimus therapy between April 2005 and July 2006 were investigated retrospectively using data from their medical records up to June 2007. The cumulative treatment continuation rate was assessed by the Kaplan–Meier method. Fisher’s exact test was used to compare gastrointestinal symptoms between different tacrolimus doses and between the presence and absence of each concomitant medication. The mean (±SD) observation period was 288 ± 238 days. The cumulative treatment continuation rate was, respectively, 59.5% and 38.1% at 6 months and 1 year after the patients started treatment. Tacrolimus was discontinued in 28 patients, and was discontinued because of adverse reactions in 21 patients. Gastrointestinal symptoms were the most common adverse reactions (45.2% = 19/42 patients), followed by infections and hyperglycemia. Tacrolimus was discontinued in 9/19 patients with gastrointestinal symptoms, and was discontinued within 60 days of starting treatment in seven of them. Nausea and vomiting led to discontinuation in seven patients (within 60 days of starting treatment in six of them). The incidence of gastrointestinal symptoms was higher in patients receiving a daily dose ≥2 mg than in those receiving <2 mg/day. During treatment of rheumatoid arthritis by oral tacrolimus therapy, gastrointestinal symptoms were common, early, and dose-dependent. However, these symptoms were not severe and did not cause any serious safety problems.     

Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate

OBJECTIVE: To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra. METHODS: Two hundred forty-four patients in whom rheumatoid arthritis (RA) was active despite methotrexate therapy were treated with subcutaneous etanercept only (25 mg twice weekly), full-dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months in a double-blind study at 41 centers in the US. Patients had never previously received anticytokine therapy. Patient response was measured with the American College of Rheumatology (ACR) core set criteria, a health-related quality-of-life questionnaire, and the Disease Activity Score. Safety was assessed by the number of adverse events and clinical laboratory values. Plasma concentrations of both agents and antibody formation against both agents were also assessed. RESULTS: Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk. Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50% response, compared with 41% of the patients treated with etanercept only. This result was not statistically significant (P = 0.914). The incidence of serious infections (0% for etanercept alone, 3.7-7.4% for combination therapy), injection-site reactions, and neutropenia was increased with combination therapy. Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent. CONCLUSION: Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.     

Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis

Objective. To assess the safety and effectiveness of leflunomide versus placebo in patients with active rheumatoid arthritis (RA) treated for 6 months. Methods. Four hundred two patients were randomly assigned to receive placebo or leflunomide at 5 mg, 10 mg, or 25 mg daily. A washout period of 6–12 weeks from prior second-line therapy was required. Results. Statistically significant improvement in primary and secondary outcome measures, as well as by responder analyses, occurred in the 10-mg and 25-mg dosage groups compared to placebo. Twenty-one patients (7.0%) in the active treatment groups withdrew due to adverse events (AEs). The incidence of AEs was higher with leflunomide than with placebo. Gastrointestinal symptoms, weight loss, allergic reactions, skin rash, and reversible alopecia were more common in the 10-mg and 25-mg dosage groups. The incidence of infections was similar between the treatment and placebo groupsno opportunistic infections were seen. Transient elevations in liver function studies were noted in a small number of patients. Conclusion. Leflunomide is effective in daily doses of 10 mg and 25-mg in patients with active RA. Improved efficacy at the 25-mg dose was associated with a higher incidence of AEs. Randomized, placebocontrolled trials using daily doses of 10 mg and 20 mg are under way in the US and Europe to confirm these positive results.     

The safety of anakinra in high-risk patients with active rheumatoid arthritis: six-month observations of patients with comorbid conditions

OBJECTIVE: To determine in a placebo-controlled, double-blind trial the safety profile of daily anakinra (Kineret) use in patients with active rheumatoid arthritis (RA) and concurrent comorbid conditions. METHODS: In 169 centers in 9 countries, 1,414 patients with active RA were randomly assigned to receive either anakinra (100 mg) or placebo treatment (4:1 anakinra-to-placebo allocation ratio), with study drug administered by daily subcutaneous injection for 6 months. The current post hoc analysis assessed baseline comorbid conditions, and patients were considered at high risk for the occurrence of adverse events if they had a history of at least one of the following: cardiovascular event, pulmonary event, central nervous system-related event, infection, diabetes, malignancy, or renal impairment. Within each treatment group (anakinra or placebo), incidence rates were summarized for serious adverse events, infectious events, and serious infectious events in high-risk patients and compared with these incidence rates in patients without comorbid conditions. RESULTS: The majority of patients in the trial had one or more comorbid conditions. In these high-risk patients, there were no differences in the incidence of serious adverse events or infectious events between treatment groups. The incidence of serious infectious events with anakinra use was similar between high-risk patients (2.5%) and the entire study population (2.1%) and was not attributable to any single comorbidity. CONCLUSION: Results of the analysis of adverse events in patients with active RA and coexisting comorbidities suggest that the favorable safety profile of anakinra is maintained in a high-risk patient population.     

Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience

OBJECTIVE: To evaluate the long-term safety of tacrolimus 3 mg/day in patients with rheumatoid arthritis (RA). METHODS: Patients with active RA who had discontinued all DMARDs for at least 2 weeks and had at least five tender/painful joints and three swollen joints, and required DMARD treatment in the opinion of the investigator, were enrolled into this open-label long-term safety trial. In addition, patients who had completed at least 3 months of treatment with tacrolimus 2 mg/day, tacrolimus 3 mg/day or placebo in a Phase III double-blind efficacy trial were allowed to roll over into this study. This latter group of patients did not have to fulfil any joint count requirements prior to entry into the long-term safety study, provided that no more than 14 days had elapsed between the end of their participation in the double-blind study and screening for the long-term safety study. All patients enrolled received tacrolimus 3 mg/day in addition to their current regimen of NSAIDs and corticosteroids. RESULTS: 896 patients received at least one dose of tacrolimus 3 mg. The median duration of treatment was 359 days. 145 patients (16.2%) withdrew from the study for adverse events possibly or probably related to tacrolimus, 33 patients (3.7%) withdrew from the study for adverse events unrelated to tacrolimus and 112 (12.5%) withdrew for lack of efficacy. No adverse event with an incidence >0.7% appeared for the first time after the first 3 months of treatment with 3 mg tacrolimus. 529 patients (59%) experienced an adverse event that was possibly or probably related to tacrolimus; the most common were diarrhoea (14.6%), nausea (10.3%), tremor (9.0%), headache (8.7%), abdominal pain (7.9%), dyspepsia (7.6%), increased creatinine (6.8%) and hypertension (5.4%). Twenty-four patients (2.7%) experienced serious adverse events possibly or probably related to study drug; the most common were pneumonia (0.6%), hyperglycaemia (0.3%), gastroenteritis (0.2%), pancreatitis (0.2%) and diabetes mellitus (0.2%). The mean creatinine level increased from 67+/-19 micromol/l (0.76+/-0.22 mg/dl) at baseline to 75+/-26 micromol/l (0.85+/-0.30 mg/dl) (P<0.0001) at end of treatment. 351 (40.3%) of the 872 patients for whom creatinine levels were available at both baseline and during treatment had > or =30% increase from baseline in serum creatinine during the study, either related or unrelated to tacrolimus, with 73 patients (8.4%) having creatinine levels exceeding the normal range. At end of treatment, 177 patients (20.3%) had a > or =30% increase from baseline in creatinine. Serum creatinine remained within the normal range throughout the trial in approximately 90% of patients. At the end of treatment, the ACR20, ACR50 and ACR70 response rates were 38.4%, 18.6% and 9.0% respectively. Over 26% of patients had at least a 70% improvement in both swollen and painful/tender joints. CONCLUSION: This study demonstrates that tacrolimus was safe and well-tolerated and provided clinical benefit over a period of at least 12 months.     

Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis

OBJECTIVE: To evaluate safety and efficacy of etanercept treatment in elderly (age > or = 65 yrs) and younger adult subjects (age < 65 yrs) with rheumatoid arthritis (RA). METHODS: Subset analyses were used to describe the safety and efficacy of etanercept in elderly and younger subjects treated for early and disease modifying antirheumatic drug-resistant or late-stage RA (ERA and LRA) in one of 4 randomized controlled clinical studies (N = 1353) or 2 longterm extensions (N = 1049). RESULTS: Rates of serious adverse events tended to be higher in elderly than younger subjects; however, rates of safety events observed in elderly etanercept-treated subjects did not exceed rates in elderly placebo or methotrexate (MTX)-treated subjects. With regard to efficacy measures [American College of Rheumatology 20% response (ACR20), ACR50, and ACR70], elderly subjects tended to have somewhat less robust responses to treatment than younger subjects. However, for both age groups, treatment with etanercept resulted in improved efficacy and function compared with control treatment, and combination therapy with etanercept plus MTX resulted in greater efficacy than either etanercept or MTX used alone. Efficacy responses of elderly subjects were sustained for up to 6 years. Radiographic progression (measured using modified Sharp Score) after one year of treatment was lower in subjects treated with both etanercept and MTX compared with subjects treated with either agent used alone, and this pattern was similar in both age groups. CONCLUSION: Consistent with responses in younger subjects, elderly subjects with RA treated with etanercept experienced significant improvement in disease activity and function without incurring additional safety concerns.     

Adalimumab treatment in patients with rheumatoid arthritis with renal insufficiency

Objective

To elucidate the safety of adalimumab for rheumatoid arthritis (RA) patients with renal insufficiency, including those with end‐stage renal disease undergoing hemodialysis.

Methods

Sixty‐five RA patients, including 2 patients undergoing hemodialysis, treated with adalimumab in our hospital from December 1, 2008 to June 30, 2011 were retrospectively analyzed. Renal function was evaluated by the estimated glomerular filtration rate (eGFR) calculated from the Cockcroft‐Gault formula at the start and end of followup after adalimumab treatment. The proportion of the patients who discontinued or switched adalimumab treatment and the change of the eGFR were compared between patients with (n = 39) and without (n = 26) renal insufficiency, defined as an eGFR <60 ml/minute/1.73 m².

Results

There was no significant difference between the 2 groups in the proportion of the patients who discontinued or switched adalimumab treatment (51.3% versus 50.0%; P = 0.53). The mean ± SD changes of eGFR were from 41.6 ± 13.3 to 43.4 ± 17.9 ml/minute/1.73 m² in patients with renal insufficiency and from 83.6 ± 17.5 to 83.0 ± 16.8 ml/minute/1.73 m² in patients without renal insufficiency, and the differences in each group were not statistically significant (P = 0.92 and P = 0.78, respectively). No severe infections or other severe adverse events were observed in either group during adalimumab treatment.

Conclusion

Our data indicate that adalimumab does not worsen renal function and has no serious adverse events even for RA patients with renal insufficiency, including those undergoing hemodialysis, and suggest that it could be a potential therapeutic option for them.     

Innovative treatment strategies for patients with rheumatoid arthritis

PURPOSE OF REVIEW: The present review provides an update on novel treatment strategies striving for remission in patients with recent onset of rheumatoid arthritis. RECENT FINDINGS: As early treatment is crucial to achieve optimal results, identifying patients with rheumatoid arthritis early is imperative to achieve clinical remission. Patients with early arthritis who will progress to rheumatoid arthritis can be identified, and treating these patients can postpone the diagnosis of rheumatoid arthritis and retard the progression of structural damage. The best way to achieve remission is by adjusting treatments at regular intervals using predetermined response criteria. Specific treatments to rapidly induce remission include disease modifying antirheumatic drugs combinations, especially combined with glucocorticoids or tumor necrosis factor antagonists. The prediction of joint damage progression, or the response to specific drugs is not yet accurately possible. The early institution of tumor necrosis factor antagonists followed by discontinuation leads to sustained clinical benefit. SUMMARY: Early treatment of patients with rheumatoid arthritis with strategies aiming at remission results in the best outcomes. Until the prediction of a severe disease course and treatment response becomes possible, a promising strategy would be to rapidly induce remission using an effective combination of drugs followed by tapering and discontinuation. Tumor necrosis factor antagonists have proven to be highly effective in this approach.     

B-cell depletion in patients with rheumatoid arthritis refractant to multiple TNF blockers and the interleukin 1 receptor-antagonist anakinra

To evaluate the efficacy of Rituximab in a negatively selected patient cohort, with inadequate response to different disease modifying drugs (DMARDs) and to at least two biologicals. Fifteen patients with severe rheumatoid arthritis with inefficacy of an average of 5 DMARDS and 2.5 TNF antagonists were treated with Rituximab. Eight patients were ineffectively pretreated with Anakinra as well. The disease activity score (DAS28) and the morning stiffness served for assessment of the clinical response. For maintenance treatment different conventional DMARDs were used (4xMTX, 4xLeflunomide, 1xmycophenolate, 1xsirolimus, 1xhydroxychloroquine). At baseline visit the mean DAS 28 was 5.9. The mean duration of morning stiffness was 99.6 min. At month 6 the mean DAS28 was 3.95. Forty percent (6 patients) showed a good and 33% (5 patients) a moderate response. Morning stiffness improved to 43 min. In this negatively selected group of patients Rituximab was safe and effective.     

Safety of biologic agents after rituximab therapy in patients with rheumatoid arthritis

The safety of other biologic therapies in rheumatoid arthritis (RA) following B cell-depletion therapy with rituximab has not been established. This retrospective chart review of patients attending an outpatient rheumatology clinic aimed to assess the incidence of adverse events in patients receiving biologic agents to treat RA after an inadequate response or intolerance to rituximab. The charts of 22 patients (18 female; mean age 59 years) were reviewed. Duration of RA was >2 years. Before rituximab, patients had failed one (n = 10), two (n = 4) or three (n = 7) biologic therapies: 1 patient started on rituximab as a first-line biologic. Eighteen patients stopped rituximab due to an inadequate clinical response, while four patients stopped due to adverse events. The mean time to starting a new biologic after rituximab was 4 months, although five patients were started within 1 month of the last rituximab infusion. Abatacept (41%) was the most common biologic used after rituximab. The mean follow-up time from the last rituximab infusion was 14 months. Adverse events occurring after rituximab therapy, but before initiation of a new biologic, included disseminated herpes zoster and aseptic meningitis (both required hospitalization). Adverse events recorded after starting a new biologic post-rituximab included rash, carbuncle, upper respiratory tract infection, urinary tract infection, pneumonia, and eczema, but none was classified as serious. Most of these events occurred in patients receiving abatacept. In conclusion, in this retrospective analysis, no serious adverse events were recorded in patients who received biologic agents following rituximab therapy.