Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition.

BACKGROUND: Neonatal-onset multisystem inflammatory disease is characterized by fever, urticarial rash, aseptic meningitis, deforming arthropathy, hearing loss, and mental retardation. Many patients have mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, encoding cryopyrin, a protein that regulates inflammation. METHODS: We selected 18 patients with neonatal-onset multisystem inflammatory disease (12 with identifiable CIAS1 mutations) to receive anakinra, an interleukin-1-receptor antagonist (1 to 2 mg per kilogram of body weight per day subcutaneously). In 11 patients, anakinra was withdrawn at three months until a flare occurred. The primary end points included changes in scores in a daily diary of symptoms, serum levels of amyloid A and C-reactive protein, and the erythrocyte sedimentation rate from baseline to month 3 and from month 3 until a disease flare. RESULTS: All 18 patients had a rapid response to anakinra, with disappearance of rash. Diary scores improved (P<0.001) and serum amyloid A (from a median of 174 mg to 8 mg per liter), C-reactive protein (from a median of 5.29 mg to 0.34 mg per deciliter), and the erythrocyte sedimentation rate decreased at month 3 (all P<0.001), and remained low at month 6. Magnetic resonance imaging showed improvement in cochlear and leptomeningeal lesions as compared with baseline. Withdrawal of anakinra uniformly resulted in relapse within days; retreatment led to rapid improvement. There were no drug-related serious adverse events. CONCLUSIONS: Daily injections of anakinra markedly improved clinical and laboratory manifestations in patients with neonatal-onset multisystem inflammatory disease, with or without CIAS1 mutations. (ClinicalTrials.gov number, NCT00069329 [ClinicalTrials.gov].).

Antirheumatic drugs and the risk of tuberculosis.

BACKGROUND: We aimed to quantify the rate of Mycobacterium tuberculosis disease (TB) among a cohort of patients with rheumatoid arthritis (RA) and to assess whether the independent use of disease-modifying antirheumatic drugs (DMARDs) is associated with the risk of developing TB. METHODS: The study was performed using the PharMetrics Patient-Centric database (PharMetrics). The cohort consisted of all subjects with > or =1 occurrence of a diagnosis of RA during an inpatient or outpatient visit during the period of September 1998 through December 2003. Conditional logistic regression was used in a nested case-control analysis to estimate the rate ratio (RR) of TB with any use of biological or traditional DMARDs during the year before the index date. We also assessed the interaction between DMARDs and the current use of corticosteroids. RESULTS: The cohort consisted of 112,300 patients with RA. A total of 386 cases of TB were identified, which resulted in an overall rate of 2.19 cases per 1000 person-years. The adjusted RR of TB for biological DMARD use is 1.5 (95% CI, 1.1-1.9). Use of traditional DMARDs was also independently associated with TB (RR, 1.2; 95% CI, 1.0-1.5). RRs of developing TB disease with the use of biological or traditional DMARD were lower among current users of corticosteroids than among noncurrent users of corticosteroids. CONCLUSION: We found that the use of biological and traditional DMARDs is associated with an increased risk of developing TB in patients with RA, mainly among noncurrent users of corticosteroids.

Safety of tumour necrosis factor and interleukin-1 blocking agents in rheumatic diseases.

The three licensed TNF(alpha) blocking agents (etanercept, infliximab, adalimumab) and the recombinant form of human interleukin-1-receptor antagonist (anakinra) have all been shown to be effective in patients with chronic rheumatic autoimmune diseases; they have also been associated with certain types of serious adverse events. As expected, much of the information on serious events have accumulated during the post-marketing period. Certain serious, but uncommon, adverse events have been observed with all three TNF(alpha) blocking agents, including serious bacterial infections, tuberculosis (TB) and certain opportunistic infections, demyelinating syndromes, and lupus-like reactions. These data suggest that these adverse reactions may be related to blockade of TNF(alpha) and may therefore represent class effects of these agents. However, the severity and degree of risk may not be the same with all three agents. Blockade of interleukin-1 activity with anakinra appears, at present, to be relatively safe. The safety profile of these products will continue to be developed through the use of the registry, periodic safety updates from the passive surveillance program, and safety data from controlled trials of biological therapy for other diseases. Physicians should minimize risks by patient selection and screening for opportunistic infections. Moreover, the choice of the biological agent must be tailored to minimize risks and maximize benefits.

Anakinra: a review of its use in the management of rheumatoid arthritis.

Anakinra (Kineret) is the first biologic drug that has been developed specifically as an interleukin (IL)-1 receptor antagonist (Ra) and is derived from an endogenous IL-1Ra. The drug blocks the activity of IL-1 in synovial joints, reducing the inflammatory and joint destructive processes associated with rheumatoid arthritis (RA). In randomized, placebo-controlled trials of up to 52 weeks' duration, anakinra has shown efficacy both as monotherapy and in combination with other disease-modifying antirheumatic drugs (DMARDs) in adults with RA. It is subcutaneously administered and is generally well tolerated. Anakinra offers a useful addition to the range of drugs available for the treatment of RA.

[Increased risk of infection with biological immunomodifying antirheumatic agents. Clear guidelines are necessary as shown by case reports]. / Okad risk för infektion med biologiska immunmodifierande antireumatika.

Several potent immunosuppressive drugs have become available in the new millennium for patients with rheumatologic diseases, Crohn's disease and other autoimmune disorders. Five patient cases from Växjö central hospital (uptake area 178 000 individuals) with Listeria meningitis, Pneumocystis jiroveci and tuberculosis pneumonia, Listeria sepsis, Legionella pneumonia and E coli sepsis are described. A doubled risk for infections has previously been observed for RA patients, as compared to healthy individuals. There is clearly an increased risk of tuberculosis (depending on the actual and historic environmental prevalence) for patients on TNF antagonists, and therefore tuberculosis screening is now mandatory before start of therapy. Since TNF has a central role in the immune defence, an increased risk of opportunistic infections like listeriosis. mycobacteriosis, and invasive fungal infections has been established. Eight hospitals in southern Sweden participate in a register for the use of TNF blockers in rheumatologic diseases (South Swedish Arthritis Treatment Group, SSATG). Guidelines for screening and treatment of latent and active tuberculosis, possible prophylactic antibiotic treatment for endocarditis and vaccination programs for patients on TNF antagonists are discussed.

Durability and rapidity of response to anakinra in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease that ultimately leads to disability and functional decline. Because patients usually develop RA in mid-life, they may experience its consequences for 20-30 years or longer. Proinflammatory cytokines, notably interleukin (IL)-1 and tumour necrosis factor-alpha, are believed to play significant pathophysiological roles. Clinical trials of biologicals that block these cytokines confirm their importance.Anakinra, a recombinant human IL-1 receptor antagonist, improves clinical signs and symptoms, and slows radiographic progression in patients with active RA. In clinical trials, patients receiving anakinra doses >1 mg/kg, whether administered alone or in combination with methotrexate, were two to three times more likely than patients receiving placebo to achieve a sustained ACR20 (American College of Rheumatology criteria) response. Notably, bone erosion slows to a greater extent and shows accelerated benefit when anakinra treatment is continued for periods beyond 24 weeks. Anakinra has a rapid onset of action, with substantial improvements in biochemical indices (C-reactive protein) seen within 1 week and clinical responses (ACR20 or joint counts) seen within 4 weeks of starting treatment. Anakinra is generally well tolerated, with injection site reactions being the most common adverse event. These reactions are generally mild and typically resolve within 2-3 weeks of treatment. The anakinra product labelling does include a warning regarding an increased risk of infections of 2% in anakinra-treated patients versus <1% in patients receiving placebo.

The safety and efficacy of interleukin-1 receptor antagonist in the treatment of rheumatoid arthritis.

BACKGROUND: Interleukin (IL)-1 has been associated with joint inflammation and damage in rheumatoid arthritis (RA). Endogenous IL-1 receptor antagonist (IL-1Ra) may inhibit IL-1-mediated effects by binding to the IL-1 receptors. OBJECTIVES: These studies were conducted to determine the efficacy and safety of human recombinant IL-1 receptor antagonist (IL-1ra) in blunting the effects of IL-1 in patients with RA. METHODS: Three randomized clinical trials have been completed. First, in a 24-week, double-blind, placebo-controlled study of 472 patients with severe RA, patients were randomly placed into 4 groups: placebo or IL-1ra at 30, 75, or 150 mg/d. In a second study, 309 patients from the placebo-controlled trial enrolled in a 24-week extension study. Patients who had been receiving placebo were randomized into 1 of the 3 treatment groups. Those receiving treatment continued to receive their previous dosages. Finally, in a second double-blind, placebo-controlled study, 419 patients with RA receiving methotrexate at 12.5 to 25 mg/wk for at least 6 months were randomly placed into 1 of 6 groups: placebo or IL-1ra at 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg/d. RESULTS: In the first study, the primary therapeutic endpoint-an American College of Rheumatology 20% response (ACR20)-was reached by 27% of the placebo group, compared with 43% of the IL-1ra 150-mg/d group. Individual clinical responses, as well as the arrest of joint damage, were also superior in treated patients. In the second trial, 52% of the randomized patients achieved an ACR20. This was maximal (71%) in those receiving the highest treatment dosage. Of patients continuing with the same dosage, 49% maintained an ACR20 at 48 weeks. Radiologic evaluation showed that the reduced rate of cartilage degradation observed in treated patients during the first 24 weeks was maintained, and the rate of joint erosion was slowed even more significantly in the second phase of the study. In the third study, significantly more patients receiving IL-1ra at 1.0 (46%, P =.001) or 2.0 (38%, P =.007) mg/kg/d achieved an ACR20 at week 12 than those receiving placebo (19%). Similar responses were noted at week 24. IL-1ra was generally well tolerated, with injection site reaction the most frequent adverse event. No serious adverse events attributable to IL-1ra treatment were observed. CONCLUSIONS: These studies suggest an important role for IL-1ra as a novel therapeutic agent in the treatment of RA.

Infection complications associated with the use of biologic agents.

Despite the considerable clinical, radiologic, and functional benefits of biologic inhibitors in inflammatory arthritides, some concern exists regarding the occurrence of infections in patients treated with these agents. Clearly, comorbidities such as diabetes mellitus, heart disease, disability, and concurrent immunosuppressive medication all contribute to the risk of infection. Increased and closer observation may be in part responsible for some of the reported increases in the rates of mild infections with these drugs. The development of serious infections, particularly TB, in patients taking infliximab seems to be greater than would be expected in this population. Furthermore, experimental data from in vitro investigations and animal models demonstrate a link between decreased TNF alpha activity and increased susceptibility to TB. Why some patients, but not others, succumb to rapidly disseminated infection is unknown but may be related to the extent of TNF inhibition in different individuals. This difference in inhibition may also explain why the incidence of TB seems to be increased with infliximab in comparison with the other TNF blockers. Attribution analysis is the method used to assess the likelihood of a connection between two occurrences and includes such factors as temporal association, few alternative explanations, analogy with similar cases, and biologic plausibility. The putative relationship between anti-TNF treatment and infection is further strengthened by the presence of these factors [101]. Continued vigilance is therefore required in the use of biologic agents in patients with RA, most of whom are already in some way immunocompromised. Everyone who is under consideration for such treatment should be carefully evaluated for the presence of infection, and prophylactic antituberculous therapy should be used if latent TB is discovered. Both patients and primary physicians need to be aware of the possibility that serious infection may develop; if such a problem is diagnosed, the biologic inhibitor should be discontinued until adequate treatment has been completed. Caution is advised in patients with recurring infections and in those with severe comorbidities, for example, poorly controlled diabetes mellitus or heart failure. Administration of live vaccines to patients taking these drugs is not recommended, but patients should be brought up-to-date with all immunizations relevant to their age group before commencement of therapy. Physicians prescribing biologic agents should be encouraged to report any suspected drug-related adverse event. Long-term observation will be required to determine the exact nature of the relationship between cytokine inhibition and infection.

Anakinra.

Anakinra, a recombinant human interleukin-1 (IL-1) receptor antagonist, is the first biological agent approved to block the pro-inflammatory effects of IL-1 in patients with rheumatoid arthritis. In a double-blind, randomised trial in 472 patients with active, severe or very severe rheumatoid arthritis, recipients of subcutaneous anakinra 150 mg/day achieved higher response rates [assessed using the American College of Rheumatology (ACR) composite score] and accumulated more mean productivity days after 6 months than placebo recipients. However, the response rates and accumulated productivity days of patients receiving subcutaneous anakinra 30 or 75 mg/day for 6 months were similar to those of placebo. With respect to the total Genant radiographic scores, the same study showed that all anakinra treatment regimens slowed disease progression after 6 months to a greater extent than placebo. In double-blind, randomised trials in patients with rheumatoid arthritis, combined treatment with anakinra and methotrexate was associated with higher ACR 20, 50 and 70 response rates than with methotrexate alone. Anakinra, used alone or in combination with methotrexate, was generally well tolerated, with the most frequent adverse event being a mild injection-site reaction of transient duration. Infections requiring antibacterial therapy or hospitalisation occurred more commonly in anakinra recipients than in placebo recipients, but were a rare cause for discontinuation of anakinra therapy (approximately 1%) in clinical trials.

The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis.

OBJECTIVES: To review the evidence of the clinical and cost-effectiveness of anakinra, an interleukin-1 receptor antagonist (IL-1Ra), for the treatment of rheumatoid arthritis (RA) in adults. DATA SOURCES: Electronic bibliographic databases. Scrip, Food and Drug Administration (FDA) submissions for new drug applications, European Agency for the Evaluation of Medicinal Products (EMEA) reports and the pharmaceutical company submission to the National Institute for Clinical Excellence. REVIEW METHODS: Studies were identified that included randomised controlled trials (RCTs) or economic evaluations of anakinra in adult patients with RA. Existing health economic reviews were also assessed. Data were extracted and quality assessed using a structured approach. The Birmingham Rheumatoid Arthritis Model (BRAM) was used to compare disease-modifying antirheumatic drug (DMARD) sequences, chosen to reflect current clinical practice, with and without anakinra, at different points in the DMARD sequence. RESULTS: Five high-quality RCTs of anakinra in adult patients with RA, involving a total of 2905 patients, of whom 2146 received anakinra, were identified. The results of the clinical trials were consistent with clinical benefit (compared with placebo) as measured by American College of Rheumatology (ACR) composite response rate at 6 months. Variation in response rate was seen across the trials, which is likely to be a reflection of the size of the trials and the wide range of doses evaluated. Consistent benefit was seen at the higher dose evaluated. Benefit was evident both with monotherapy and when used in combination with methotrexate. Data on the efficacy end-points evaluated in a large pragmatic safety study have not been made available, which is of concern. Anakinra treatment was associated with a high incidence of injection-site reactions. Serious adverse events were infrequent, but longer term follow-up is required. No fully published economic evaluations of anakinra in patients with RA were identified. The BRAM gives a base-case estimate of the incremental cost-effectiveness ratio (ICER) of anakinra of 106,000 pounds to 604,000 pounds/quality-adjusted life-year (QALY). In the sensitivity analyses substantial variations were made in key parameters and ICERs were shown to be responsive. However, ICERs did not drop below 50,000 pounds/QALY in any univariate sensitivity analysis. CONCLUSIONS: Anakinra can be considered modestly effective in the treatment of RA based on ACR response, although no conclusion can currently be made on the effect of treatment on disease progression. Adjusted indirect comparison suggests that anakinra may be significantly less effective at relieving the clinical signs and symptoms of RA, as measured by the ACR response criteria, than tumour necrosis factor (TNF) inhibitors all used in combination with methotrexate, although these results should be interpreted with caution. The BRAM produces an ICER for anakinra substantially higher than those for infliximab and etanercept. However, patients may respond to anakinra when they have not responded to other TNF inhibitors, as these agents have a different mechanism of action. Thus, anakinra may produce a clinically significant and important improvement in some patients that they could not otherwise have achieved. Further research would be valuable in the following areas: RCTs to evaluate the efficacy, safety and cost of anakinra over the longer term; comparative trials of anakinra with other DMARDs and biological modifiers; assessment of the role of anakinra in the treatment of patients who have failed to achieve a benefit while taking infliximab or etanercept; assessment on the impact of DMARDs and anakinra on joint replacement, mortality and quality of life; controlled clinical trials of combination therapy with two anticytokines; investigations into newer biological therapies; and the utility of radiographic outcomes in clinical trials of RA.

Infections and biological therapy in rheumatoid arthritis.

Infections are common in patients with rheumatic disorders. Reasons for such vulnerability include alterations of immunoregulation, disease severity, debility, co-morbid illnesses and the use of immunosuppressive medications. The advent of new biological agents has precipitated a further examination of the links between infection, the underlying disease and its treatment, resulting in several interesting observations. Interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF-alpha), the major pro-inflammatory cytokines, play important roles in host defence against infection. Inhibition of their activity could therefore be anticipated to augment the risk of infection in patients with pre-existing abnormalities of immune regulation. Slight increases in the rates of infection were noted in the clinical trials of IL-1 receptor antagonist (IL-1Ra). In addition, a small number of opportunistic infections have been observed with the TNF inhibitor, etanercept. However, a marked increase in opportunistic infection, particularly tuberculosis, has occurred with the use of infliximab, an agent that also blocks TNF activity. The precise mechanisms by which these agents predispose to infection are currently being explored. The answers are likely to add significantly to our knowledge of how immune dysfunction contributes both to the pathophysiology of disease and the complications of therapy.

Overview of benefit/risk of biological agents.

Targeted tumor necrosis factor-alpha antagonists, first approved by the FDA in 1998, have had a significant impact on the treatment of patients with rheumatoid arthritis. In general, the benefit/ risk ratio for these agents and the IL-1 receptor antagonist, anakinra, has been quite favorable. However, infrequent adverse events can be serious and require continued pharmacovigilance. Infections, particularly tuberculosis and less commonly fungal infections, are among the most serious adverse events, especially given delays in diagnosis due to subtle or atypical presentations. Questions have also arisen regarding whether anti-TNF-alpha agents increase the risk of lymphoma, a complicated issue confounded by the multiple risk factors for lymphoma in patients with rheumatoid arthritis and low observed incidence rates of lymphoma, requiring prolonged monitoring. Additional rare reported complications include systemic lupus erythematosus-like syndromes, congestive heart failure and demyelinating syndromes (including cases resembling progressive multifocal leukoencephalopathy). Ongoing post-marketing surveillance of these and other serious adverse events is necessary to determine the true incidence rates, and whether a reassessment of the overall risk-benefit of tumor necrosis factor-alpha antagonists will be required.

Safety of anakinra, a recombinant interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis and comparison to anti-TNF-alpha agents.

Anakinra is a recombinant human interleukin-1 receptor antagonist (IL-1ra) recently approved by the FDA as a new therapy for patients with rheumatoid arthritis. Four clinical trials have been completed which have demonstrated that anakinra is an effective anti-rheumatic therapy either used alone or in combination with methotrexate. The most frequent adverse events reported in the clinical trials are injection-site reactions which are generally mild to moderate and rapidly resolve. A large, prospective safety study which allowed a wide-variety of comorbid conditions and concomitant medications demonstrated that anakinra therapy is a well-tolerated treatment for rheumatoid arthritis in the patient population seen by the practicing rheumatologist. Unlike therapies designed to affect TNF-alpha, there have not yet been reports of the development of tuberculosis or other fungal infections, demylinating syndromes or worsening of congestive heart failure. The safety profile of etanercept and infliximab were similar to that of anakinra in the phase I-phase III clinical trials. Unlike anakinra, these medications were not studied in the usual rheumatoid arthritis population which includes a number of patients with a wide variety of co-morbid disease and utilizing a number of concomitant anti-rheumatic medications. Post approval, several safety concerns, including patients at risk for serious infection and the emergence of latent tuberculosis and other opportunistic infections have emerged with the use of anti TNF therapy.

Effect of sulglycotide in the prevention of duodenal ulcer relapse.

OBJECTIVE: To evaluate the effectiveness of sulglycotide, a gastroprotective drug, as maintenance treatment for patients with duodenal ulcer. DESIGN: A randomized double-blind study. METHODS: A total of 119 patients with recently healed duodenal ulcers were randomly allocated, in a double-blind fashion, to receive sulglycotide 200 mg twice daily (60 patients) or placebo (59 patients) for 1 year. Patients underwent clinical assessment every third month and endoscopy at 6 and 12 months, or earlier if relapse was suspected. RESULTS: The cumulative endoscopic relapse rates, compared using the log rank test, were 37 and 52% after 6 and 12 months, respectively, in the sulglycotide group and 62 and 71% (P = 0.03), respectively, in the placebo group. CONCLUSIONS: Sulglycotide is moderately effective as a maintenance treatment for duodenal ulcer disease.

Biologic agents for the treatment of juvenile rheumatoid arthritis: current status.

Biologic therapies, primarily anticytokine therapies, are being increasingly used in patients with juvenile rheumatoid arthritis (JRA). Levels of a variety of proinflammatory cytokines have been shown to be elevated in the peripheral blood and synovial fluid and tissue in children with JRA. In a blinded, randomized, controlled trial in children with severe, long-standing, polyarticular-course JRA not responsive to standard therapies, etanercept showed a statistically significantly greater response rate than placebo. Approximately 75% of these children responded to etanercept. Etanercept has been efficacious in 50-60% of children with active systemic JRA in open clinical trials with acceptable tolerance. Adverse events seen in children treated with etanercept have been similar in type and frequency to those reported in adults. Infliximab has been studied in several open clinical trials in both polyarticular and systemic JRA and found to, overall, have demonstrated efficacy in approximately 60% of patients. Approximately 3-5% of patients have demonstrated infusion reactions or frank allergic reactions and 9% developed new autoantibodies. Anakinra has been studied in children with polyarticular JRA. Approximately 65% of patients developed injection-site reactions and 68% demonstrated a response to the medication. Anakinra may have increased efficacy in systemic JRA. Interleukin (IL)-6 is highly related to the systemic disease manifestations in systemic JRA and two patients treated with a monoclonal antibody to the IL-6 receptor have demonstrated significant improvement with prolonged clinical control with continued treatment. A particular pediatric concern is the effect of immunosuppressive biologics in children who are exposed to or develop varicella. These children should be treated, both in terms of prophylaxis and aggressive antivaricella treatment, as for other immunosuppressed children. Anticytokine biologics have demonstrated great promise in the treatment of JRA and a variety of other pediatric rheumatic diseases, although at this time the randomized, placebo-controlled data are limited only to etanercept in children with polyarticular JRA. Randomized trials are ongoing to better define both the efficacy and safety of these novel treatments for children with JRA and other rheumatic diseases.

Kineret: efficacy and safety in daily clinical practice: an interim analysis of the Kineret response assessment initiative (kreative) protocol.

Data from 166 patients who had completed 6 months of anakinra (Kineret, r-metHuIL-1Ra) therapy under the conditions of daily clinical practice showed an efficacy and safety profile comparable to the data known from clinical trials. Patients significantly responded as early as 1 month following initiation of therapy. The data suggest that anakinra may also be effective in patients who have failed tumor necrosis factor (TNF)-blocking agents. Injection-site reactions were reported less frequently than in clinical trials, indicating that these reactions seem to require less therapeutic attention under non-clinical trial conditions.

[The safety of interleukin-1 receptor antagonist (anakinra) in the treatment of rheumatoid arthritis]. / Sicurezza e tollerabilità dell'antagonista del recettore dell'interleuchina-1 nel trattamento dell'artrite reumatoide.

The safety profile of interleukin-1 receptor antagonist (anakinra) has been studied with randomised, placebo-controlled trials involving 2932 patients affected by rheumatoid arthritis. The most frequently reported adverse events were represented by injection site reactions (71%) and headache (13.6%). No statistically significant difference in the incidence of infections was observed among the patients treated with the interleukin-1 receptor antagonist and the patients receiving placebo. In particular, the incidence of serious infections was 1,8% in rheumatoid arthritis patients on anakinra therapy and 0,7% in patients on placebo. The reported serious infections consisted of pneumonia, cellulitis, bone and joint infections, bursitis. No case of opportunistic infections or tubercolosis was observed. The results of clinical studies suggest that anakinra is a new well-tolerated drug for the treatment of patients affected by rheumatoid arthritis.

Anakinra: new preparation. Weakly effective in rheumatoid arthritis.

(1) There is no consensus on the best treatment option for rheumatoid arthritis when a first-line agent fails (most often methotrexate). Among the recent immunosuppressants, etanercept should be used before infliximab. (2) Anakinra, an interleukin-1 type 1 receptor antagonist, was recently authorised in the European Union as a second-line treatment for rheumatoid arthritis in combination with methotrexate. (3) There are no published trials comparing anakinra with other slow-acting antirheumatic drugs (especially infliximab and etanercept). In one clinical trial in patients who did not respond adequately to methotrexate, the combination anakinra + methotrexate was more effective than methotrexate + placebo on ACR 20%, ACR 50% and ACR 70% criteria, but the clinical relevance of these results is doubtful. (4) An indirect comparison suggests that etanercept is more effective than anakinra + methotrexate. (5) In a placebo-controlled trial of anakinra, 75% of patients had reactions at the injection site. Serious infections, neutropenia and anti-anakinra antibodies were also reported. There is no evidence that anakinra is any safer than etanercept. (6) Anakinra + etanercept offers no gains in efficacy, just an increased risk of severe infections. (7) Subcutaneous injections of anakinra are required daily (twice-weekly subcutaneous injections for etanercept). (8) In short, there is no argument for using anakinra as a second-line treatment for rheumatoid arthritis; it does not improve disease management.

[Therapeutic use of "biologics" in inflammatory joint and spinal diseases]. / Therapeutischer Einsatz von "Biologics" bei entzündlichen Gelenk- und Wirbelsäulenerkrankungen.

At present, two principles of biologic treatment for rheumatoid arthritis and other chronic inflammatory joint and spine diseases (juvenile polyarticular idiopathic arthritis, spondarthritides) are available for use in clinical practice. These are the TNF-alpha antagonists etanercept and infliximab as well as the human recombinant IL-1 receptor antagonist anakinra. All three biologics have significant short and long-term therapeutic effects on clinical and humoral inflammatory activity compared to placebo treatment in controlled clinical trials and even radiological progression of rheumatoid arthritis can be with halted. Principally, safety and tolerability of TNF- and IL-1 antagonist are good. However, local skin reactions at injection sites and infections of the upper respiratory tract and urinary tract have to be considered. Severe infections are rare except for an increased frequency of tuberculous infection observed with infliximab worldwide. The induction of autoantibodies including antibodies to double-stranded DNA and neuralizing antibodies to etanercept and infliximab themselves can occur though their clinical significance is still upon debate. It is important to notice that the advantages of the use of biologics in individual patients has carefully to be balanced against their high costs and the increased risk of infectious side effects. Therefore, guidelines of international experts recommend the clinical use of biologics mostly for patients resistant or intolerable to conventional treatment.

What are the risks of biologic therapy in rheumatoid arthritis? An update on safety.

The tumor necrosis factor-alpha (TNF-alpha) blockers infliximab and etanercept and the recombinant interleukin 1 (IL-1) receptor antagonist anakinra are effective in patients with active rheumatoid arthritis (RA). Here, information in the medical literature and public domain is used to consider the safety of these biologic agents. TNF-alpha inhibition with infliximab has been associated with reactivation of tuberculosis and possibly development of other opportunistic infections (histoplasmosis, listeriosis. and pneumocystis). Exacerbations of multiple sclerosis and other central nervous system events have been reported with etanercept and infliximab. Recently, a review of preliminary data from an ongoing phase II study suggests that infliximab may worsen congestive heart failure. On the basis of clinical trials, there appears to be a higher incidence of serious infections seen in anakinra patients compared with controls; the particular combination of anakinra and etanercept may be associated with a higher incidence of serious infections and clinically significant leukopenia. Additional data are needed to understand whether all these safety issues are unique to an individual biologic agent or representative of a class effect. At this time, treating physicians must carefully weigh the benefits of these new biologics against their risks, particularly in patients at risk of infection.