Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated analysis from clinical trials.

OBJECTIVE: To report the long-term safety data of certolizumab pegol (CZP) in rheumatoid arthritis (RA) accumulated as of 30 November 2011. DESIGN: Data from 10 completed randomised controlled trials (RCT) of CZP in RA and several open-label extensions (OLE) were pooled across all doses. Reported adverse events (AE) occurred between the first dose and 84 days after the last dose. All deaths, serious infectious events (SIE) and malignancies were reviewed by external experts, classified according to predefined rules, and validated by an external steering committee. Incidence rates (IR) and event rates (ER) per 100 patient-years (PY) are presented. RESULTS: 4049 RA patients who received CZP were included in the safety pooling; total exposure 9277 PY, mean exposure 2.1 years (range 0.04-7.6). SIE, most frequently pneumonia (IR 0.73/100 PY), were the most common serious AE, occurring more frequently in CZP compared to placebo-treated patients in RCT (IR 5.61/100 PY vs 1.35/100 PY, odds ratio (OR) 4.35, 95% CI 0.65 to 29.30). SIE rates were lower in the CZP-treated population including OLE (ER 4.33/100 PY). 44 patients developed tuberculosis (IR 0.47/100 PY), 39 from high endemic regions. 58 deaths occurred in CZP-exposed patients (IR 0.63/100 PY) and 70 developed malignancies excluding non-melanoma skin cancer (IR 0.76/100 PY), including five lymphomas (IR 0.05/100 PY). CONCLUSIONS: No new or unexpected safety signals associated with CZP emerged in this updated long-term safety analysis. While SIE rates were higher for CZP than for placebo in RCT, the rate decreased with continued exposure to CZP. These rates are consistent with data previously reported for CZP and other tumour necrosis factor inhibitors.

Laboratory monitoring of biologic therapies.

The purpose of this report is to provide suggested guidance concerning the monitoring of TNF blocker therapy. Since the completion of randomized trials, several new long-term safety concerns have arisen, involving mycobacterial and opportunistic infections, cytopenias, lymphoma, demyelinating disease, drug-induced lupus, congestive heart failure and hepatotoxicity. Since these serious events are rare, widespread post-marketing use and prolonged follow-up have been required to analyze their prevalence. Monitoring of TNF inhibitors is necessary to reassure physicians and patients of the continued efficacy and safety of these drugs. No published recommendations on monitoring are available. The clinician must weigh the potential clinical benefits of TNF inhibition against potential adverse effects. Patients should be evaluated carefully for the risk or presence of infection, tuberculosis and other serious adverse events by regular visits, careful clinical assessments, and an assiduous, high index of suspicion for these rare events. Tuberculin skin testing using PPD is recommended before starting treatment with any TNF inhibitor.

Biological drug use: US perspectives on indications and monitoring.

An estimated 20% of patients with rheumatoid arthritis (RA) receive tumour necrosis factor (TNF) inhibitor treatment. This paper presents the results of an online survey of US rheumatologists (1023 respondents) conducted in April 2005 on issues relating to use of TNF inhibitors in RA. The primary determinant of TNF inhibitor use among the participating rheumatologists was physician preference rather than patient preference or payor guidelines. Qualitative (rather than quantitative measures) assessments (physician overall assessment, symptom review, etc.) and laboratory measures were more frequently employed when assessing and treating patients with RA. Clinical assessments with hepatic enzymes and complete blood count as an additional safety tool were most commonly employed to monitor drug safety. Nearly all the rheumatologists (> or = 92%) felt that a partial purified derivative (PPD) test was indicated when using a TNF inhibitor, but were equally split with regard to those with a history of PPD positivity or BCG vaccination. The frequency of serious adverse events was estimated and included tuberculosis, systemic fungal infection, demyelinating disorders, cytopenia, drug induced lupus, lymphoma, and hepatic failure. Among 454 RA patients who became pregnant while receiving biological therapy there were 378 normal deliveries, 9 premature babies, 5 therapeutic abortions, and 25 miscarriages. It was concluded that a greater than expected number of US rheumatologists are familiar with biologicals and TNF inhibitor therapies, but uncertainties and educational gaps still exist regarding their use and monitoring.

Sustained durability and tolerability of etanercept in ankylosing spondylitis for 96 weeks.

OBJECTIVE: To evaluate the continued safety and durability of clinical response in patients with ankylosing spondylitis receiving etanercept. METHODS: 277 patients who had participated in a previous randomised, double blind, placebo controlled 24 week trial were eligible to continue in this open label extension study. All patients who enrolled in the open label extension (n = 257) received subcutaneous etanercept 25 mg twice weekly for up to 72 weeks, for a combined 96 weeks of cumulative trial and open label experience. For the patients who had received etanercept for 24 weeks in the double blind trial, this represented almost 2 years of continuous etanercept treatment. RESULTS: Patients continuing etanercept treatment had a sustained response for almost 2 years, with 74% achieving an ASsessments in Ankylosing Spondylitis 20% (ASAS 20) response after 96 weeks of etanercept treatment. Patients who had received placebo in the preceding double blind trial had similar responses, with 70% of patients attaining an ASAS 20 response after 24 weeks of etanercept treatment and 78% achieving an ASAS 20 response after 72 weeks. Improved spinal mobility was seen in both groups. Etanercept was well tolerated in patients treated for up to 96 weeks. CONCLUSION: The subcutaneous administration of twice weekly doses of etanercept provided sustained durability of response in the improvement of signs and symptoms of ankylosing spondylitis for nearly 2 years.

Unusual toxicities with TNF inhibition: heart failure and drug-induced lupus.

Serious and unexpected adverse events, such as heart failure and drug-induced lupus, have been reported in patients receiving TNF inhibitor therapy. These events generally are easily recognizable, although they cannot be predicted nor avoided, other than by drug avoidance altogether Many patients have great benefit from anti-TNF therapies. Their intelligent use requires a firm understanding of these rare toxicities, so as to minimize the morbidity associated with their uncommon occurrence.

A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate.

OBJECTIVE: To assess the efficacy and safety of 100 mg daily anakinra (Kineret), a recombinant form of the naturally occurring interleukin 1 receptor antagonist, plus methotrexate (MTX) in reducing the signs and symptoms of rheumatoid arthritis (RA). METHODS: Patients with active RA (n = 506) despite current treatment with MTX were enrolled in this multicentre, double blind, randomised, placebo controlled study. Patients received subcutaneous injections of anakinra 100 mg/day or placebo. They were assessed monthly for 6 months for improvement in signs and symptoms of RA and for adverse events. The primary efficacy measure was the percentage of patients attaining ACR20 response at week 24. RESULTS: Significantly greater proportions of patients treated with anakinra compared with placebo achieved ACR20 (38% v 22%; p<0.001), ACR50 (17% v 8%; p<0.01), and ACR70 (6% v 2%; p<0.05) responses. The response to anakinra was rapid; the proportion of patients with an ACR20 response at the first study assessment (4 weeks) was twice as high with anakinra as with placebo (p<0.005). Clinically meaningful and statistically significant responses were also seen in individual components of the ACR response (for example, Health Assessment Questionnaire, pain, C reactive protein levels, and erythrocyte sedimentation rate). Anakinra was well tolerated, with a safety profile, similar to that of placebo with one exception: mild to moderate injection site reactions were more common with anakinra than with placebo (65% v 24%). CONCLUSIONS: This study confirms previous observations from a dose-ranging study showing that anakinra, in combination with MTX, is an effective and safe treatment for patients with RA who have inadequate responses to MTX alone.

The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis.

OBJECTIVE: To report the safety and efficacy of leflunomide (LEF) in combination with infliximab (INF) for the treatment of rheumatoid arthritis. METHODS: In an open, multicenter, retrospective study, data were collected on the safety and efficacy of LEF and INF. RESULTS: Eighty-eight patients received the combination of LEF and INF for an average of 6.6 months and a total exposure of 581 patient-months. The mean duration of LEF was 17 +/- 9 months (range 3-32 months; median 18.5 months) with an average of 4.8 INF infusions per patient. In all but 3 subjects, LEF was used initially and INF was added later. Infusion reactions occurred in 3 patients (0.7% of all infusions). A total of 34% of subjects experienced adverse events and in 6 (6.8% of the group) these were deemed serious. Ten infections occurred when patients were taking the combination; 9 patients recovered fully and 1 died of bacterial pneumonia. A lifetime smoker developed lung cancer and another patient was found to have colon cancer. CONCLUSIONS: The adverse events noted within the combination therapy group were in keeping with the known risks of each drug when used individually. Limited data were available on efficacy, but a general improvement in disease control was noted with the combination of drugs, which for most patients involved the addition of INF to previous use of LEF.

Early arthritis clinic: a USA perspective.

An early arthritis clinic (EAC) was established to identify early rheumatoid arthritis (RA) patients for clinical trials and to create a facile method of early patient referral from the practitioner to the rheumatologist. With minimal advertising and promotion, patients with less than 12 months of symptoms were easily referred if the primary care physician suspected a rheumatic condition. Of those patients who were appropriately referred one-third had synovitis, 20% had diagnostic cutaneous findings, 20% were diagnosed with lupus (or lupus-like disease), 12.5% had RA, and 10% were diagnosed with a spondyloarthropathy. An EAC was easily established, implemented and staffed and resulted in the prompt diagnosis and early treatment of many patients who may have otherwise waited months for appropriate rheumatologic diagnosis and treatment.

A phase I study of ethyl acetate extract of the chinese antirheumatic herb Tripterygium wilfordii hook F in rheumatoid arthritis.

OBJECTIVE: To explore the efficacy and safety of ethyl acetate (EA) extracts of the Chinese herbal remedy Tripterygium wilfordii Hook F (TWHF) for treatment of patients with a variety of inflammatory and autoimmune diseases including rheumatoid arthritis (RA). METHODS: The roots of TWHF were extracted sequentially by ethyl alcohol and ethyl acetate and the content of the extract documented. An open label, dose escalation Phase I study was performed in 1993 in 13 patients with established RA. Clinical manifestations and laboratory findings were examined before and every 4 weeks after starting treatment with the EA extract. RESULTS: Three patients withdrew from the trial during the first 16 weeks of the dose escalation. These patients received a maximum dosage of 180 mg/day. There were no adverse effects or disease improvement observed in these patients. Nine of the remaining 10 patients tolerated the EA extract up to a dosage of 570 mg/day. There were no withdrawals related to adverse events in the trial except for one patient who developed diastolic hypertension at a dose of 180 mg/day of EA extract. Six of 10 patients treated with 180 mg/day of EA extract showed disease improvement. Eight of the 9 patients who received EA extract at doses > 360 mg/day experienced improvement in both clinical manifestations and laboratory findings. One patient met American College of Rheumatology criteria for remission. CONCLUSION: The EA extract of TWHF at dosages up to 570 mg/day appeared to be safe, and doses > 360 mg/day were associated with clinical benefit in patients with RA.

Rheumatoid synovial CD4+ T cells exhibit a reduced capacity to differentiate into IL-4-producing T-helper-2 effector cells.

CD4+ memory T cells (Tm) from rheumatoid arthritis peripheral blood (RAPB) or peripheral blood from normal donors produced IL-2, whereas fewer cells secreted IFN-gamma or IL-4 after a brief stimulation. RAPB Tm contained significantly more IFN-gamma producers than normal cells. Many rheumatoid arthritis (RA) synovial Tm produced IFN-gamma alone (40%) and fewer cells produced IL-2 or IL-4. An in vitro model was employed to generate polarized T-helper (Th) effectors. Normal and RAPB Tm differentiated into both IFN-gamma- and IL-4-producing effectors. RA synovial fluid (RASF) Tm demonstrated defective responsiveness, exhibiting diminished differentiation of IL-4 effectors, whereas RA synovial tissue (RAST) Tm exhibited defective generation of IFN-gamma and IL-4 producers.

US consensus guidelines for the use of cyclosporin A in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that often leads to irreversible joint damage and loss of function. Although there are numerous treatment options, it is difficult to manage the disease in most patients. Use of cyclosporin A (CsA) for RA was first reported in 1979, and since that time many trials have investigated CsA use for this disease. Based on clinical evidence, CsA is an efficacious second-line agent for patients with active RA who have not responded adequately to methotrexate (MTX). In addition, CsA has been shown to provide clinical benefit when used in combination with MTX in patients responding inadequately to MTX monotherapy. Side effects associated with CsA treatment are manageable if dosing, monitoring, and intervention guidelines are followed. The purpose of this review is to provide recommendations for the use of CsA in severe RA to physicians experienced in the management of systemic immunosuppressive therapy for RA. Where possible and appropriate, recommendations are based on evidence available in the literature.

Rationale and risks of novel immunomodulatory therapies in rheumatoid arthritis.

The need for new therapies for the treatment of rheumatoid arthritis (RA) has arisen during an era where clinicians have realized that RA is a far more ominous condition than was thought previously. The last decade has revealed numerous studies depicting the limited long-term efficacy and tolerability of conventional disease-modifying antirheumatic drug (DMARD) therapies. Moreover, DMARDs have not been shown to be truly capable of modifying articular, functional and radiographic outcomes in patients with RA. These issues have been raised amidst significant advances in our understanding of the immunopathogenesis of RA and advances in biotechnology. Such advances have led to a revised approach to using conventional DMARDs, while new pharmacologic and biospecific interventions are being developed. This chapter will discuss the clinical and biologic rationale for novel therapies for patients with RA and the hazards imposed by the therapeutic manipulation of various immune effector mechanisms in patients with RA.

An evidence-based medicine approach to the diagnosis and management of musculoskeletal complaints.

Evidence-based medicine is an approach to clinical practice and teaching that emphasizes decision-making based on rigorous analysis of clinical research tailored to the individual characteristics of a specific patient. As such, it can be considered the scientifically grounded art of medicine. Through evidence-based guidelines, pathways, and algorithms, the care of populations of patients may also be facilitated by informing individual practitioners of optimal decision-making in specific situations or providing the foundation for comprehensive "disease management" programs. These programs coordinate care for patients with chronic conditions, such as rheumatoid arthritis and osteoarthritis, across time and multiple disciplines. We present an approach to the development of decision-making aids, including guidelines and algorithms, which should be helpful in the care of individual patients and populations for whom physicians and other healthcare practitioners are responsible.

Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis. A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active ankylosing spondylitis (AS) that is not controlled with nonsteroidal antiinflammatory drug therapy. METHODS: Two hundred sixty-four patients with AS were recruited from 15 clinics, randomized (double-blind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on morning stiffness, back pain, and physician and patient global assessments. RESULTS: While longitudinal analysis revealed a trend favoring SSZ in the middle of treatment, no difference was seen at the end of treatment. Response rates were 38.2% for SSZ and 36.1% for placebo (P = 0.73). The Westergren erythrocyte sedimentation rate declined more with SSZ treatment than with placebo (P < 0.0001). AS patients with associated peripheral arthritis showed improvement that favored SSZ (P = 0.02). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints. CONCLUSION: SSZ at a dosage of 2,000 mg/day does not seem to be more effective than placebo in the treatment of AS patients with chronic, longstanding disease. SSZ is well tolerated and may be more effective than placebo in the treatment of AS patients with peripheral joint involvement. This effect is more pronounced in treatment of the peripheral arthritis in this subgroup of AS patients.

Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active psoriatic arthritis (PsA) resistant to nonsteroidal antiinflammatory drug therapy. METHODS: Two hundred twenty-one patients with PsA were recruited from 15 clinics, randomized (double-blind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on joint pain/ tenderness and swelling scores and physician and patient global assessments. RESULTS: Longitudinal analysis revealed a trend favoring SSZ treatment (P = 0.13). At the end of treatment, response rates were 57.8% for SSZ compared with 44.6% for placebo (P = 0.05). The Westergren erythrocyte sedimentation rate declined more in the PsA patients taking SSZ than in those taking placebo (P < 0.0001). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints, including dyspepsia, nausea, vomiting, and diarrhea. CONCLUSION: SSZ at a dosage of 2,000 mg/day is well tolerated and may be more effective than placebo in the treatment of patients with PsA.