Live polio vaccine exposure while receiving anti‐TNF therapy for reactive arthritis

International guidelines state that live vaccines are contraindicated in patients on anti‐TNF therapy. However, we report the experience of a patient who inadvertently received live polio vaccine whilst receiving anti‐TNF therapy. Patient did not suffer from any infectious sequel as a result. No clear guidelines are available for all vaccines in patients with specific rheumatic diseases. However, if we consider adult patients with rheumatic diseases to have altered immunocompetence, it is recommended that they receive the usual inactivated vaccines according to standard schedules, and live vaccines should be avoided in those who are treated with more potent forms of immune suppression. Patients should be counseled regarding the risks of live vaccines prior to treatment with anti‐TNF therapy.     

Tuberculosis and biologics in rheumatology: A special situation

India has a huge patient burden of rheumatic diseases (RDs) including rheumatoid arthritis. The use of biologics has transformed the treatment paradigm for RD; however, biologic treatment‐related infections (especially tuberculosis [TB]) are an area of potential concern for TB‐endemic nations like India. Anti‐tumor necrosis factor (TNF) therapy impairs the physiological TNF‐mediated signaling and may cause reactivation and dissemination of latent TB infection (LTBI). Careful screening is, thus, crucial in RD patients who are about to commence anti‐TNF treatment. To date, there is no consensus available for the screening, evaluation and treatment of LTBI as well as on the drug dosage and duration regimen (monotherapy or combination therapy) in the Indian population. An evidence‐based algorithm for LTBI screening and management in RD patients undergoing biologic disease‐modifying anti‐rheumatic drug therapy is suggested in this review for Indian rheumatologists. The proposed algorithm guides physicians through a step‐wise screening approach, including medical history, tuberculin skin test, interferon gamma release assay, chest radiograph and management of LTBI with isoniazid therapy or its combination with rifampicin. Further, the provided algorithm can aid the national bodies (such as National TB Control Program) in formulating recommendations for LTBI in this high‐risk population.     

Anti‐tumor necrosis factor biosimilars and intended copies in rheumatology: Perspective from the Asia Pacific region

Although anti‐tumor necrosis factor (TNF) agents have greatly improved the management of rheumatic diseases, their cost limits access to many patients throughout the world. As a result, patients and clinicians have turned to biosimilars to provide similar efficacy at a lower cost. Many of the regulatory guidelines in the Asia Pacific region are largely based on those of the European Medicines Agency and the World Health Organization; however, there are variations between countries. Additionally, in some countries, intended copies are available that were approved prior to the development of guidelines and have not fulfilled the requirements of a biosimilar. We review the various regulatory requirements for biosimilars in the Asia Pacific region, the anti‐TNF biosimilars and intended copies approved in the region, and whether clinical data are available for these agents. We discuss concerns about the need for additional regulations and education, and we provide recommendations for a multidisciplinary pharmacovigilance approach that closely monitors the safety of biosimilar use.     

Updated consensus statement on tumour necrosis factor blocking agents for the treatment of rheumatoid arthritis and other rheumatic diseases (April 2001)

TNF blocking agents have proved to be effective DMARDs and they have been a major advance in the treatment of RA. Their use is expanding to other rheumatic diseases. However, rare to uncommon and unexpected toxicities have been found and others may yet be found during their use. Studies in selected areas of efficacy, toxicity, and general use of TNF blocking agents are needed to help further define the most appropriate use of these agents. Use of these drugs will require doctors experienced in the diagnosis, treatment, and assessment of RA and other rheumatic diseases. These doctors will need to make long term observations of efficacy and toxicity. Further considerations which must be made when using TNF blocking agents in this disease include the cost and a recognition that data in subgroups are still being acquired. It is hoped that this statement, which is based upon the best evidence available at the time of its creation, and modified by expert opinion, will facilitate the optimal use of these agents for our patients with RA and other rheumatic diseases.     

Extended indications for anti‐tumor necrosis factor‐α therapy

Tumour necrosis factor‐α is a pleiotropic cytokine which has a broad range of actions in inflammation, infection and immunity. TNF‐α is supposed to play a crucial role in the pathogenesis of various autoimmune diseases. TNF‐α blocking agents have been demonstrated to be highly effective in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis. TNF‐α inhibitors also have been tried with other rheumatic diseases and have emerged as promising treatments. We here review the current evidences of effectiveness of the anti‐TNF‐α therapy in various autoimmune diseases.     

Experience of antitumor necrosis factor‐α therapies in Taiwan

Background: Etanercept (Enbrel), was the first approved biologics in Taiwan for rheumatoid arthritis (RA), juvenile RA (JRA), psoriatic arthritis and ankylosing spondylitis. Approximately 500 patients with RA were under etanercept therapy by April 2006. Aim: We aimed to review the current status of biological agents use in the treatment of rheumatic diseases in Taiwan. Methods: MEDLINE database (January 1966 to February 2006) was searched by MeSH terms, limited to Taiwan by author affiliations. All known principal clinical investigators and pharmaceutical companies in Taiwan were contacted for unpublished information about this issue. Results: Six articles including two clinical trials, two case series and two preclinical studies were found in MEDLINE since January 1966. A 12‐week double‐blind placebo‐controlled study of 58 patients with active adult RA in Taiwan revealed better efficacy than results in Western countries. For JRA, two studies reported good results in polyarticular type JRA but fair response in systemic type. Adalimumab (Humira, Abbott) and Alefacept (Ameviev, Biogen) had completed their local trials in RA and psoriasis but they are not yet available in Taiwan. Widespread usage of biologics has been limited due to restricted insurance coverage policy only to the refractory patients with RA. Some herbs demonstrating TNF‐α inhibition properties are under exploratory clinical trials. Conclusions: Etanercept showed better efficacy in patients with adult RA in Taiwan than Western countries. Some herbs demonstrated TNF‐α inhibition and are under laboratory and clinical investigations.     

Adverse effects of tumour necrosis factor‐α blocking agents

Tumor necrosis factor α (TNF‐α) blocking agents have been proved to be very effective in the treatment of various inflammatory rheumatic diseases which are refractory to conventional disease‐modifying antirheumatic drugs. However, anti‐TNF‐α therapy may have adverse effects on host defence against infectious agents in which TNF‐α plays a pivotal role. In addition, there are reports about neurologic, autoimmune, cardiac, and malignant diseases associated with TNF‐α blocking agents. This article summarizes the adverse effects and safety of these agents.     

Practical guidelines for treating inflammatory bowel disease safely with anti‐tumour necrosis factor therapy in Australia

Anti‐tumour necrosis factor (TNF) therapy is an effective but expensive option for treating inflammatory bowel disease (IBD). Its use is generally reserved for patients with severe refractory disease, often involving long‐term administration. Anti‐TNF therapy has the potential to be associated with various adverse effects, such as infection, malignancy and immunogenicity. Clinicians and patients should be familiar with these possibilities and adopt appropriate precautions prior to and during treatment to minimize risk. Guidelines have been developed for Australian prescribers intending to use anti‐TNF therapy in IBD by a Working Party commissioned by IBD‐Australia, a Special Interest Group affiliated with the Gastroenterology Society of Australia.     

Asian Organization for Crohn's and Colitis and Asian Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti‐tumor necrosis factor treatment. Part 1: Risk assessment

Because anti‐tumor necrosis factor (anti‐TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti‐TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asian Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection, and prevention of latent TB infection and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti‐TNF treatment. Twenty‐three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web‐based consensus voting was performed by 211 IBD specialists from nine Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 1 of the statements comprised two parts: (i) risk of TB infection during anti‐TNF therapy and (ii) screening for TB infection prior to commencing anti‐TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti‐TNF treatment.     

Asian Organization for Crohn's and Colitis and Asia Pacific Association of Gastroenterology consensus on tuberculosis infection in patients with inflammatory bowel disease receiving anti‐tumor necrosis factor treatment. Part 2: Management

Because anti‐tumor necrosis factor (anti‐TNF) therapy has become increasingly popular in many Asian countries, the risk of developing active tuberculosis (TB) among anti‐TNF users may raise serious health problems in this region. Thus, the Asian Organization for Crohn's and Colitis and the Asia Pacific Association of Gastroenterology have developed a set of consensus statements about risk assessment, detection and prevention of latent TB infection, and management of active TB infection in patients with inflammatory bowel disease (IBD) receiving anti‐TNF treatment. Twenty‐three consensus statements were initially drafted and then discussed by the committee members. The quality of evidence and the strength of recommendations were assessed by using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Web‐based consensus voting was performed by 211 IBD specialists from nine Asian countries concerning each statement. A consensus statement was accepted if at least 75% of the participants agreed. Part 2 of the statements comprised three parts: (3) management of latent TB in preparation for anti‐TNF therapy, (4) monitoring during anti‐TNF therapy, and (5) management of an active TB infection after anti‐TNF therapy. These consensus statements will help clinicians optimize patient outcomes by reducing the morbidity and mortality related to TB infections in patients with IBD receiving anti‐TNF treatment.     

Tumour necrosis factor in synovial exudates.

The actions of tumour necrosis factor (TNF) include resorption of bone and cartilage, suggesting a potential role in the pathogenesis of arthritis. TNF activity was looked for in synovial fluids from 137 patients with different rheumatic diseases. Unfractionated samples were tested in the L929 bioassay. Significant TNF activity that was neutralised by monoclonal antibody to TNF alpha occurred in 13 (30%) of 44 samples. Raised TNF levels were not associated with any particular disease type or routine laboratory markers of inflammation but were related to disease duration in osteoarthritis. The finding of biologically active TNF in symptomatic joints of arthritic patients supports the idea that it may contribute to the pathogenesis of joint damage in chronic rheumatic diseases.     

Use of anti-tumour necrosis factor agents in inflammatory bowel disease. European guidelines for 2001-2003

The introduction of novel anti-tumor necrosis factor (TNF) agents has not only led to impressive new therapeutic opportunities but also resulted in uncertainty regarding their optimal use and possible side effects. Guidelines are presented here for the use of anti-TNF agents in gastrointestinal disorders. Experts were chosen from different European countries by an algorithm to avoid bias. An expert consensus on guidelines was established using a two-stage procedure of systematic Medline and abstract search for evidence and a qualifying meeting to derive recommendations. Detailed guidelines were developed for the use and the future clinical development of anti-TNF agents in inflammatory bowel disease. Grading of available evidence and grading of recommendations were performed according to AHCPR guidelines. At present infliximab is the only registered agent for Crohn's disease. Infliximab should be always used at a dose of 5 mg/kg. The guidelines define the indications both in refractory and in fistulating disease for the readministration and before surgery. Guidelines for safety and for concomitant treatments are given. Prospects, potential clinical use, and future directions for the clinical development of other anti-TNF agents are detailed. Clinical use of anti-TNF agents will be influenced by a large number of clinical trials being concluded in 2001 and 2002. It is likely that anti-TNF therapies will become an important long-term therapy for a proportion of patients with Crohn's disease. Biological agents will be followed by smaller and more stable, orally available compounds. These guidelines will be succeeded by a formal public consensus in 2002/2003.     

Novel agents in the future: Therapy beyond anti‐TNF agents in inflammatory bowel disease

Anti‐tumor necrosis factor (TNF)‐α agents emerge as the hot spot in the last decade for treating patients with inflammatory bowel disease (IBD). The effect of anti‐TNF‐α agents is satisfactory; however, some patients fail to achieve clinical response. Fortunately, in recent years, great efforts have been made and multiple novel therapies have been developed in the treatment for IBD. In this article, we aim to introduce anti‐TNF‐α drugs as well as other novel treatments currently undergoing clinical trials for IBD.     

The use of anti‐tumour necrosis factor‐α therapies for rheumatoid arthritis in Singapore

Anti‐tumour necrosis factor‐α (anti‐TNF‐α) agents are biologic disease‐modifying antirheumatic drugs (DMARDs) used in the treatment of moderate to severe rheumatoid arthritis (RA). We describe the demographic and therapeutic profiles of 22 patients who received anti‐TNF‐α therapy for RA in two hospitals in Singapore. The majority of patients were female, middle‐aged, full‐time working adults with limitation in their social or vocational activities. The mean RA disease duration was 101.4 ± 101.6 months (3.4–401.3). All received conventional DMARDs for a mean of almost 7 years before starting anti‐TNF‐α, with the majority having failed two or more DMARDs. The most commonly used anti‐TNF‐α therapies were infliximab (90.9%), etanercept (18.2%) and adalimumab (4.5%). Only one patient developed a major infection, while three developed minor infections requiring temporary cessation of anti‐TNF‐α therapy. There were no cases of malignancy, drug‐induced lupus, demyelinating disease or congestive heart failure during an average of 36.9 ± 21.9 months (3.9–63.0) from initiation of therapy.     

PANLAR consensus statement on biosimilars

Introduction

Biologics have improved the treatment of rheumatic diseases, resulting in better outcomes. However, their high cost limits access for many patients in both North America and Latin America. Following patent expiration for biologicals, the availability of biosimilars, which typically are less expensive due to lower development costs, provides additional treatment options for patients with rheumatic diseases. The availability of biosimilars in North American and Latin American countries is evolving, with differing regulations and clinical indications.

Objective

The objective of the study was to present the consensus statement on biosimilars in rheumatology developed by Pan American League of Associations for Rheumatology (PANLAR).

Methods

Using a modified Delphi process approach, the following topics were addressed: regulation, efficacy and safety, extrapolation of indications, interchangeability, automatic substitution, pharmacovigilance, risk management, naming, traceability, registries, economic aspects, and biomimics. Consensus was achieved when there was agreement among 80% or more of the panel members. Three Delphi rounds were conducted to reach consensus. Questionnaires were sent electronically to panel members and comments about each question were solicited.

Results

Eight recommendations were formulated regarding regulation, pharmacovigilance, risk management, naming, traceability, registries, economic aspects, and biomimics.

Conclusion

The recommendations highlighted that, after receiving regulatory approval, pharmacovigilance is a fundamental strategy to ensure safety of all medications. Registries should be employed to monitor use of biosimilars and to identify potential adverse effects. The price of biosimilars should be significantly lower than that of reference products to enhance patient access. Biomimics are not biosimilars and, if they are to be marketed, they must first be evaluated and approved according to established regulatory pathways for novel biopharmaceuticals.

Key Points

• Biologics have improved the treatment of rheumatic diseases.

• Their high cost limits access for many patients in both North America and Latin America.

• Biosimilars typically are less expensive, providing additional treatment options for patients with rheumatic diseases.

• PANLAR presents its consensus on biosimilars in rheumatology

     

Anti‐tumor necrosis factor therapy: the Australian experience

Anti‐tumor necrosis factor (TNF) therapy for the management of rheumatic diseases has been reimbursed in Australia progressively per agent and disease indication since 2003. Initial projections of uptake were grossly overestimated. In this article the anti‐TNF experience in Australia is reviewed, including results of an eligibility study, Australian Rheumatology Association guidelines, anti‐TNF registry, and a report of adverse effects. These observations may assist APLAR countries currently coming to terms with anti‐TNF drug registration and funding.     

Paradoxical psoriasiform reactions of anti‐tumour necrosis factor therapy in inflammatory bowel disease patients

Anti‐tumour necrosis factor (TNF) agents have demonstrated efficacy in inflammatory bowel disease (IBD). Cutaneous reactions such as new onset psoriasis or psoriasiform‐like reactions are among the most common adverse reactions. We retrospectively identified cases of anti‐TNF‐induced psoriasis or psoriasiform manifestations in IBD patients at a tertiary centre in Australia. A total of 10 (six females) of 270 (3.7%) IBD patients treated with anti‐TNF therapy developed drug‐induced psoriatic or psoriasiform‐like reactions: five patients were treated with infliximab and five with adalimumab; nine had Crohn disease. The time from initiation of anti‐TNF agent to onset of rash was 7.5 months on average. The most frequent distributions were the scalp (7/10) and extremities (6/10). Three patients discontinued anti‐TNF treatment with resolution of the rash. Topical treatment of the lesions allowed continued use of biological agent in the majority. Paradoxical psoriatic lesions are recognised adverse events associated with anti‐TNF therapy, but discontinuation of therapy due to dermatological complications is required only rarely, even in patients with psoriasiform lesions.     

Non‐tumor necrosis factor biological therapies for rheumatoid arthritis

The emergence and use of the biological agents is one of the major recent advances in the treatment of rheumatoid arthritis. Although the tumour necrosis factor alpha (TNF‐α) inhibitors are superior to conventional disease‐modifying antirheumatic drugs (DMARDs) in terms of efficacy, certain patients may still be unresponsive or intolerant to them. Moreover, infection such as tuberculosis and the possibility of long‐term adverse effects such as malignancies are major concerns of the anti‐TNF‐α agents. Thus, newer and, hopefully, more effective but less toxic biological agents have to be developed as alternative therapies. This article reviews the preliminary clinical data on several non‐TNF‐α biological agents in the treatment of rheumatoid arthritis.