About 15 years ago, the first anti-tumor necrosis factor (anti-TNF) drugs received approval for treating Crohn disease and rheumatoid arthritis, and a new era of pharmacotherapy was born. A few years before that, I was at a meeting discussing the potential benefits and pitfalls of these new biologic therapies, and I opined that no one would pay for them on an ongoing basis unless they were amazingly effective—which was unlikely, as the drugs only affected a single cytokine. And if they were effective, they would undoubtedly be associated with a host of opportunistic infections. Given my predictive skills, it is no surprise that Warren Buffett rarely calls to ask my opinion.

Clearly, anti-TNF drugs are effective and have raised the bar for how we define successful response to therapy. But recent studies in early rheumatoid arthritis indicate that they may not be much better than traditional combination therapy or monotherapy with methotrexate if the methotrexate and the other drugs are given and tolerated at full dose. This is clearly not the case for other inflammatory diseases.

Anti-TNF drugs and other biologics are now part of the arsenal of most medical specialists, so outpatient internists and hospitalists increasingly encounter patients taking these drugs. Since patients with systemic inflammatory disease have an increased prevalence of cardiovascular disease, cardiologists are also seeing more patients taking these drugs. Thus, the overview by Hadam et al in this issue of the Journal on the risks of biologic therapies is relevant to many readers.

Almost all prescriptions and requests for insurance approval for these drugs are written by subspecialists familiar with their risks. But patients may ask their primary care physicians about the tests and vaccines recommended for those about to start anti-TNF therapy. Before starting anti-TNF therapy, all patients should be tested for previous exposure to tuberculosis and should be treated for latent tuberculosis if appropriate. Blocking TNF leads to a breakdown of the protective granulomatous inflammatory response that contains the mycobacteria and, as with corticosteroid treatment, results in reactivation of the disease. Interestingly, the reactivation is quite often not in the lungs. And since anti-TNF therapy dramatically blunts the inflammatory response, as does corticosteroid therapy, reactivation may appear as nonspecific malaise or may be misinterpreted as a flare in the underlying disease, and thus it may go undiagnosed. Patients should also be screened for exposure to hepatitis B virus. Vaccines, particularly live vaccines, are generally given if possible before starting anti-TNF therapy, and all patients on chronic therapy should get annual influenza vaccines.

Despite initial concerns about a dramatically increased risk of routine and opportunistic infections in patients on anti-TNF therapy, this has not been observed. Even in the perioperative setting, the increased risk of infection is modest. What has struck me, however, is the way these drugs, like steroids, blunt and mask the signs of infection. I have seen deep soft-tissue, intra-abdominal, and native and prosthetic joint infections go unsuspected for days or even weeks in the absence of significant fever, elevation in acute-phase markers, or dramatic local findings. We must be extra vigilant.

There is a fear of malignancy arising or recurring in patients on anti-TNF therapy. This fear is certainly promoted by the required black-box warning about the risk of lymphoma and other malignancies that these drugs carry. The evidence of a significant increase in risk of malignancies other than hepatosplenic T-cell lymphoma in children and nonmelanoma skin cancers is not strong and is likely slanted by an increased risk of certain malignancies associated with the underlying rheumatic disease and other previous therapies. Nonetheless, I am reluctant to use these drugs in patients with a history of melanoma.

We still have much to learn about these drugs. Why are specific agents more effective in some diseases than others? For example, etanercept treats rheumatoid arthritis but not Crohn disease. Also, we still do not know how they can elicit reversible demyelinating disorders or autoantibodies with or without associated drug-induced lupus syndromes. Even odder is the occurrence of psoriasis induced by anti-TNF drugs, despite their being used to treat psoriasis.

My initial skepticism regarding anti-TNF drugs was unjustified. They are being tested and used successfully in an increasing number of diseases. But we all need to increase our familiarity with their unique risks and somehow find a way to deal with their unique cost.

About 15 years ago, the first anti-tumor necrosis factor (anti-TNF) drugs received approval for treating Crohn disease and rheumatoid arthritis, and a new era of pharmacotherapy was born. A few years before that, I was at a meeting discussing the potential benefits and pitfalls of these new biologic therapies, and I opined that no one would pay for them on an ongoing basis unless they were amazingly effective—which was unlikely, as the drugs only affected a single cytokine. And if they were effective, they would undoubtedly be associated with a host of opportunistic infections. Given my predictive skills, it is no surprise that Warren Buffett rarely calls to ask my opinion.

Clearly, anti-TNF drugs are effective and have raised the bar for how we define successful response to therapy. But recent studies in early rheumatoid arthritis indicate that they may not be much better than traditional combination therapy or monotherapy with methotrexate if the methotrexate and the other drugs are given and tolerated at full dose. This is clearly not the case for other inflammatory diseases.

Anti-TNF drugs and other biologics are now part of the arsenal of most medical specialists, so outpatient internists and hospitalists increasingly encounter patients taking these drugs. Since patients with systemic inflammatory disease have an increased prevalence of cardiovascular disease, cardiologists are also seeing more patients taking these drugs. Thus, the overview by Hadam et al in this issue of the Journal on the risks of biologic therapies is relevant to many readers.

Almost all prescriptions and requests for insurance approval for these drugs are written by subspecialists familiar with their risks. But patients may ask their primary care physicians about the tests and vaccines recommended for those about to start anti-TNF therapy. Before starting anti-TNF therapy, all patients should be tested for previous exposure to tuberculosis and should be treated for latent tuberculosis if appropriate. Blocking TNF leads to a breakdown of the protective granulomatous inflammatory response that contains the mycobacteria and, as with corticosteroid treatment, results in reactivation of the disease. Interestingly, the reactivation is quite often not in the lungs. And since anti-TNF therapy dramatically blunts the inflammatory response, as does corticosteroid therapy, reactivation may appear as nonspecific malaise or may be misinterpreted as a flare in the underlying disease, and thus it may go undiagnosed. Patients should also be screened for exposure to hepatitis B virus. Vaccines, particularly live vaccines, are generally given if possible before starting anti-TNF therapy, and all patients on chronic therapy should get annual influenza vaccines.

Despite initial concerns about a dramatically increased risk of routine and opportunistic infections in patients on anti-TNF therapy, this has not been observed. Even in the perioperative setting, the increased risk of infection is modest. What has struck me, however, is the way these drugs, like steroids, blunt and mask the signs of infection. I have seen deep soft-tissue, intra-abdominal, and native and prosthetic joint infections go unsuspected for days or even weeks in the absence of significant fever, elevation in acute-phase markers, or dramatic local findings. We must be extra vigilant.

There is a fear of malignancy arising or recurring in patients on anti-TNF therapy. This fear is certainly promoted by the required black-box warning about the risk of lymphoma and other malignancies that these drugs carry. The evidence of a significant increase in risk of malignancies other than hepatosplenic T-cell lymphoma in children and nonmelanoma skin cancers is not strong and is likely slanted by an increased risk of certain malignancies associated with the underlying rheumatic disease and other previous therapies. Nonetheless, I am reluctant to use these drugs in patients with a history of melanoma.

We still have much to learn about these drugs. Why are specific agents more effective in some diseases than others? For example, etanercept treats rheumatoid arthritis but not Crohn disease. Also, we still do not know how they can elicit reversible demyelinating disorders or autoantibodies with or without associated drug-induced lupus syndromes. Even odder is the occurrence of psoriasis induced by anti-TNF drugs, despite their being used to treat psoriasis.

My initial skepticism regarding anti-TNF drugs was unjustified. They are being tested and used successfully in an increasing number of diseases. But we all need to increase our familiarity with their unique risks and somehow find a way to deal with their unique cost.

About 15 years ago, the first anti-tumor necrosis factor (anti-TNF) drugs received approval for treating Crohn disease and rheumatoid arthritis, and a new era of pharmacotherapy was born. A few years before that, I was at a meeting discussing the potential benefits and pitfalls of these new biologic therapies, and I opined that no one would pay for them on an ongoing basis unless they were amazingly effective—which was unlikely, as the drugs only affected a single cytokine. And if they were effective, they would undoubtedly be associated with a host of opportunistic infections. Given my predictive skills, it is no surprise that Warren Buffett rarely calls to ask my opinion.

Clearly, anti-TNF drugs are effective and have raised the bar for how we define successful response to therapy. But recent studies in early rheumatoid arthritis indicate that they may not be much better than traditional combination therapy or monotherapy with methotrexate if the methotrexate and the other drugs are given and tolerated at full dose. This is clearly not the case for other inflammatory diseases.

Anti-TNF drugs and other biologics are now part of the arsenal of most medical specialists, so outpatient internists and hospitalists increasingly encounter patients taking these drugs. Since patients with systemic inflammatory disease have an increased prevalence of cardiovascular disease, cardiologists are also seeing more patients taking these drugs. Thus, the overview by Hadam et al in this issue of the Journal on the risks of biologic therapies is relevant to many readers.

Almost all prescriptions and requests for insurance approval for these drugs are written by subspecialists familiar with their risks. But patients may ask their primary care physicians about the tests and vaccines recommended for those about to start anti-TNF therapy. Before starting anti-TNF therapy, all patients should be tested for previous exposure to tuberculosis and should be treated for latent tuberculosis if appropriate. Blocking TNF leads to a breakdown of the protective granulomatous inflammatory response that contains the mycobacteria and, as with corticosteroid treatment, results in reactivation of the disease. Interestingly, the reactivation is quite often not in the lungs. And since anti-TNF therapy dramatically blunts the inflammatory response, as does corticosteroid therapy, reactivation may appear as nonspecific malaise or may be misinterpreted as a flare in the underlying disease, and thus it may go undiagnosed. Patients should also be screened for exposure to hepatitis B virus. Vaccines, particularly live vaccines, are generally given if possible before starting anti-TNF therapy, and all patients on chronic therapy should get annual influenza vaccines.

Despite initial concerns about a dramatically increased risk of routine and opportunistic infections in patients on anti-TNF therapy, this has not been observed. Even in the perioperative setting, the increased risk of infection is modest. What has struck me, however, is the way these drugs, like steroids, blunt and mask the signs of infection. I have seen deep soft-tissue, intra-abdominal, and native and prosthetic joint infections go unsuspected for days or even weeks in the absence of significant fever, elevation in acute-phase markers, or dramatic local findings. We must be extra vigilant.

There is a fear of malignancy arising or recurring in patients on anti-TNF therapy. This fear is certainly promoted by the required black-box warning about the risk of lymphoma and other malignancies that these drugs carry. The evidence of a significant increase in risk of malignancies other than hepatosplenic T-cell lymphoma in children and nonmelanoma skin cancers is not strong and is likely slanted by an increased risk of certain malignancies associated with the underlying rheumatic disease and other previous therapies. Nonetheless, I am reluctant to use these drugs in patients with a history of melanoma.

We still have much to learn about these drugs. Why are specific agents more effective in some diseases than others? For example, etanercept treats rheumatoid arthritis but not Crohn disease. Also, we still do not know how they can elicit reversible demyelinating disorders or autoantibodies with or without associated drug-induced lupus syndromes. Even odder is the occurrence of psoriasis induced by anti-TNF drugs, despite their being used to treat psoriasis.

My initial skepticism regarding anti-TNF drugs was unjustified. They are being tested and used successfully in an increasing number of diseases. But we all need to increase our familiarity with their unique risks and somehow find a way to deal with their unique cost.

Biologic agents such as those that block tumor necrosis factor (TNF) alpha have revolutionized the treatment of autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease, dramatically improving disease control and quality of life. In addition, they have made true disease remission possible in some cases.

However, as with any new therapy, a variety of side effects must be considered.

WHAT ARE BIOLOGIC AGENTS?

Biologic agents are genetically engineered drugs manufactured or synthesized in vitro from molecules such as proteins, genes, and antibodies present in living organisms. By targeting specific molecular components of the inflammatory cascade, including cytokines, these drugs alter certain aspects of the body’s inflammatory response in autoimmune diseases. Because TNF inhibitors are the most widely used biologic agents in the United States, this review will focus on them.

TNF INHIBITORS

TNF inhibitors suppress the inflammatory cascade by inactivating TNF alpha, a cytokine that promotes inflammation in the intestine, synovial tissue, and other sites.^1,2

Several TNF inhibitors are available. Etanercept and infliximab were the first two to receive US Food and Drug Administration (FDA) approval, and they are extensively used. Etanercept, a soluble TNF receptor given subcutaneously, was approved for treating rheumatoid arthritis in 1998. Infliximab, a chimeric monoclonal antibody (75% human and 25% mouse protein sequence) given intravenously, received FDA approval for treating Crohn disease in 1998 and for rheumatoid arthritis in 1999. Other anti-TNF agents with varying properties are also available.

Table 1 lists anti-TNF agents approved for treating rheumatoid arthritis and inflammatory bowel disease. These are chronic, relapsing diseases that significantly and dramatically reduce quality of life, especially when they are poorly controlled.^3,4 Untreated disease has been associated with malignancy, infection, pregnancy loss, and malnutrition.^5–8 TNF inhibitors are aimed at patients who have moderate to severe disease or for whom previous treatments have failed, to help them achieve and maintain steroid-free remission. However, use of these agents is tempered by the risk of potentially serious side effects.

Special thought should also be given to the direct costs of the drugs (up to $30,000 per year, not counting the cost of their administration) and to the indirect costs such as time away from work to receive treatment. These are major considerations in some cases, and patients should be selected carefully for treatment with these drugs.

BEFORE STARTING THERAPY

Before starting anti-TNF therapy, several steps can reduce the risk of serious adverse events.

Take a focused history

The clinical history should include inquiries about previous bacterial, fungal, and tuberculosis infections or exposure; diabetes; and other immunocompromised states that increase the risk of acquiring potentially life-threatening infections.

Details of particular geographic areas of residence, occupational exposures, and social history should be sought. These include history of incarceration (which may put patients at risk of tuberculosis) and residence in the Ohio River valley or in the southwestern or midwestern United States (which may increase the risk of histoplasmosis, coccidioidomycosis, and other fungal infections).

Bring vaccinations up to date

Age-appropriate vaccinations should be discussed and given, ideally before starting therapy. These include influenza vaccine every year and tetanus boosters every 10 years for all and, as appropriate, varicella, human papillomavirus, and pneumococcal vaccinations. The US Centers for Disease Control and Prevention recommend an additional dose of the pneumococcal vaccine if more than 5 years have elapsed since the first one, and many clinicians opt to give it every 5 years.

In general, live-attenuated vaccines, including the intranasal influenza vaccine, are contraindicated in patients taking biologic agents.⁹ For patients at high risk of exposure or infection, it may be reasonable to hold the biologic agent for a period of time, vaccinate, and resume the biologic agent a month later.

Recent data suggest that the varicella zoster vaccine may be safely given to older patients with immune-mediated diseases such as rheumatoid arthritis and inflammatory bowel disease taking biologic agents.¹⁰ New guidelines from the American College of Rheumatology recommend age-appropriate vaccines for rheumatoid arthritis patients age 60 and older before biologic treatments are started. Case-by-case discussion with the subspecialist and the patient is recommended.

Screen for chronic infections

Tuberculosis screening with a purified protein derivative test or an interferon-gamma-release (Quantiferon) assay followed by chest radiography in patients with a positive test is mandatory before giving a TNF inhibitor.

Hepatitis B virus status should be determined before starting anti-TNF therapy.¹¹

Hepatitis B vaccination has been recommended for patients with inflammatory bowel disease, but no clear recommendation exists for patients with rheumatic disease. Patients with inflammatory bowel disease tend to have low rates of response to hepatitis B vaccination^12,13; possible reasons include their lack of an appropriate innate immune response to infectious agents, malnutrition, surgery, older age, and immunosuppressive drugs.¹⁴ An accelerated vaccination protocol with recombinant hepatitis B vaccine (Energix-B) in a double dose at 0, 1, and 2 months has been shown to improve response rates.¹⁵

Whenever possible, it may be better to vaccinate patients before starting immunosuppressive therapy, and to check postvaccination titers to ensure adequate response.

A full physical examination with special attention to skin rashes should be performed. This may serve as a baseline to assist early detection of new rashes associated with anti-TNF therapy.

A baseline complete blood cell count and complete metabolic panel should be routinely obtained before starting therapy (and thereafter at the discretion of the physician). In conjunction with follow-up tests, they can help detect an unexpected decrease in white blood cell count or abnormal results on the liver panel.¹⁶ These baseline and follow-up tests are generally performed by the subspecialist, and the results are shared with the primary care physician.

Table 2 summarizes key information to be sought before starting a patient on a TNF inhibitor.

ADVERSE EFFECTS OF ANTI-TNF DRUGS

Infusion reactions, infections, cardiac arrhythmias, demyelinating disorders, skin infections, and malignancies have been reported with anti-TNF therapy. The relative frequencies of these adverse events are summarized in Table 3.^17–22

NONINFECTIOUS COMPLICATIONS OF TNF INHIBITORS

Injection site reactions

When anti-TNF agents are given subcutaneously, injection site reactions are common (occurring in up to 40% of patients) and are considered minor.¹¹ Reactions, including significant pain, typically occur within the first few months of therapy. They can last 2 to 5 days but rarely warrant stopping therapy. Treatment with ice and an antihistamine is almost always sufficient to control symptoms.

Infusion reactions with infliximab

Infliximab can cause both acute and delayed infusion reactions. Acute reactions can occur up to 24 hours after infusion but usually appear within 10 minutes of administration and are handled by the infusion suite staff. They range from the severe immunoglobulin E-mediated type I reaction, manifesting with hypotension, bronchospasm, and urticaria, to the milder anaphylactoid-type reaction, which constitutes the majority.^23–25

While most primary care physicians will not encounter an acute reaction, family doctors and emergency room physicians may encounter delayed reactions, which can develop 1 to 14 days after infusion. These reactions usually resemble serum sickness and present with joint pain, fatigue, myalgia, and fever. But, unlike classic serum sickness, these reactions are generally not associated with a rash.

With nonspecific symptoms, the diagnosis may be easy to overlook. However, establishing this diagnosis is important because repeat therapy may result in a more severe reaction upon reexposure to the drug.

Once diagnosed, these reactions can be treated symptomatically with a combination of acetaminophen and diphenhydramine after discussion between the primary care physician and subspecialist.^23,24

Autoimmune syndromes

Several studies have reported a small percentage of patients treated with anti-TNF agents who develop paradoxical autoimmune conditions. These range from asymptomatic immunologic alterations, including the formation of antinuclear antibodies and antibodies to double-stranded DNA, to life-threatening systemic autoimmune diseases.^26,27

Autoimmune diseases associated with anti-TNF treatment include a lupus-like syndrome, vasculitides, and psoriatic skin lesions. These syndromes warrant stopping the inciting drug and, on occasion, giving corticosteroids. Most cases arise between 1 month and 1 year of starting treatment, and almost 75% resolve completely after the anti-TNF therapy is stopped.²⁶

Interestingly, anti-TNF agents are approved for treating psoriasis and psoriatic arthritis, but psoriasis has paradoxically developed in patients being treated with these drugs for other autoimmune diseases. The FDA has reviewed 69 cases of new-onset psoriasis with anti-TNF therapy, including 17 pustular and 15 palmoplantar cases. The 12 most severe cases resulted in hospitalization, and symptoms resolved in most after treatment cessation.²⁸

Fiorino et al²⁹ counted 18 reported cases of psoriasis induced by anti-TNF therapy in patients with inflammatory bowel disease and concluded that it is rare. Harrison et al³⁰ reported similar findings in patients with rheumatoid arthritis, with an increased incidence rate of 1.04 per 1,000 person-years. New-onset psoriasis was most common in patients treated with adalimumab. An example of the rash is seen in Figure 1.

CARDIOVASCULAR SIDE EFFECTS

Cardiovascular side effects of anti-TNF agents range from nonspecific and asymptomatic arrhythmias to worsening of heart failure.

Circulating levels of TNF are increased in patients with heart failure, and studies have evaluated the effects of TNF inhibition with infliximab on cardiac function and overall survival.^31,32 The combined risk of death from any cause or hospitalization from heart failure was significantly higher in the infliximab groups, and the effects persisted for up to 5 months after stopping therapy.

Other studies^22,33 have evaluated the effects of infliximab and etanercept on cardiac function and overall survival. Results showed possible exacerbation of heart failure with etanercept and increased risk of death with infliximab in patients with New York Heart Association (NYHA) class III or IV heart failure and left ventricular ejection fractions less than 35%.

Case reports have also described patients with worsening or new-onset heart failure on TNF inhibitors, including patients younger than 50 years and without identifiable cardiovascular risk factors.

Data analyses^31,34,35 from large clinical registries have reported no significant increase in heart failure attributable to TNF inhibitors. However, we have concerns about the methodology of these analyses.

Currently, anti-TNF therapy is contraindicated in patients with NYHA class III or IV heart failure. Data are inconclusive for patients with class I or II heart failure. Baseline echocardiography and cardiology consultation can be considered, with close monitoring and avoidance of high doses of TNF inhibitors. If heart failure develops in a patient on anti-TNF therapy, the drug should be discontinued and the patient should be evaluated further.³⁶

DEMYELINATING DISEASE, INCLUDING MULTIPLE SCLEROSIS

Anti-TNF agents have been associated with the onset or exacerbation of clinical symptoms and radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis.^37–40 Mohan et al³⁸ identified 19 cases of demyelinating events occurring after administration of anti-TNF agents in early 2001. In most cases, symptoms improved or resolved after therapy was stopped.

Optic neuritis,^41,42 bilateral optic neuropathy,⁴³ and aseptic meningitis⁴⁴ have also been reported, but these have occurred only rarely.

How common are these effects? Postmarketing surveillance in patients with rheumatoid arthritis yields an estimated incidence of demyelinating disorders of 1 per 1,000 patient-years with adalimumab therapy.⁴⁵ Complicating the assessment is an observed slight increase in risk of demyelinating conditions associated with inflammatory bowel disease.

Symptoms that should heighten the physician’s suspicion of this adverse effect include confusion, paresthesias, and ataxia. Patients on anti-TNF therapy who develop new visual symptoms should be checked for painless visual loss as a sign of early demyelinating disease.

Although data that conclusively link anti-TNF agents to multiple sclerosis are lacking, these drugs should not be initiated in patients who have a history of demyelinating disease, and treatment should be stopped promptly if the diagnosis is suspected.

MALIGNANCY

Whether anti-TNF therapy is directly linked to development of malignancies is difficult to determine. There are many confounding factors, including the risk of malignancy in underlying inflammatory disease and the concomitant use of other medications such as thiopurines, which have a known association with lymphoma.⁴⁶

The incidence of lymphoma is twice as high in rheumatoid arthritis patients as in the general population.⁴⁷ The risk is higher in those with more aggressive joint disease—the subset of rheumatoid arthritis patients who are more likely to be given anti-TNF agents.⁵

In patients with inflammatory bowel disease, the risk of cholangiocarcinoma is four times higher, and the risk of small-bowel adenocarcinoma is 16 to 18 times higher, but no increased risk of lymphoma has been identified in this population.^48,49

Data from six clinical trials of infliximab, including a long-term study of its safety in Crohn disease, suggest it poses no increase in overall risk of malignancy.^50–52 Similar results have been reported in patients with other rheumatic diseases.⁸ Information on this topic is constantly evolving, and studies range from case series to clinical trials to large patient registries.

The decision to use a TNF inhibitor should be based on the patient’s clinical picture and risk factors. Discussion of the risks and benefits of therapy with the patient should be clearly documented.

Non-Hodgkin lymphoma

Evidence about the risk of lymphoma with anti-TNF use is mixed, as up to two-thirds of patients on anti-TNF therapy have received concomitant nonbiologic immunosuppressive medications, making it difficult to determine the true risk from the biologic agents alone.⁵³ Current evidence both supports^9,53–56 and refutes^7,55,57–60 the idea that anti-TNF agents increase lymphoma risk.

In patients with inflammatory bowel disease, several population-based studies have not shown a clear increase in lymphoma risk with anti-TNF use.^56,59,60 Pedersen et al,⁶¹ in a meta-analysis of eight studies, confirmed these findings by showing no overall lymphoma risk in patients with inflammatory bowel disease.

However, a Canadian population-based study found a statistically significant increase in non-Hodgkin lymphoma in males with Crohn disease, with an incidence ratio of 3.63 (95% confidence interval [CI] 1.53–8.62).⁶¹ Additionally, Siegel et al⁶² found a significantly higher risk (6.1 cases per 10,000 patients) in patients treated with anti-TNF agents and thiopurines than in the general population (1.9 cases per 10,000 people). Although the difference was statistically significant, the overall risk is still very low.

Patients with rheumatoid arthritis seem to have a risk of lymphoma two to three times higher than in the general population. However, large population-based studies have not shown a statistically significant increase in the risk of lymphoma with anti-TNF therapy.⁶³

Hepatosplenic T-cell lymphoma is a rare subtype of peripheral T-cell non-Hodgkin lymphoma; 25 cases have been reported in patients receiving anti-TNF therapy.⁶⁴ Although the risk is extremely low (< 0.05%), physicians must carefully consider the risks and benefits of combination therapy, especially in young male patients with inflammatory bowel disease, since death is the usual outcome of this disease.^65–67

Skin cancers

Wolfe and Michaud⁸ evaluated malignancy risk in rheumatoid arthritis patients being treated with biologic agents, including TNF inhibitors, using a large longitudinal database. These data were compared with those of the US Surveillance, Epidemiology, and End-Results (SEER) national database. No increase in the overall cancer rate was seen in rheumatoid arthritis patients (standardized incidence ratio [SIR] 1.0, 95% CI 1.0–1.1).

However, melanoma was more common in rheumatoid arthritis patients compared with SEER rates (SIR 1.7, 95% CI 1.3–2.3).⁸ In addition, biologic therapy was associated with a higher (but not statistically significant) risk of melanoma (odds ratio [OR] 2.3, 95% CI 0.9–5.4) and a higher risk of nonmelanoma skin cancer (OR 1.5, 95% CI 1.2–1.8), but not of other types of cancer.⁸

INFECTION

Patients on anti-TNF therapy are at a higher risk of infection, ranging from minor to life-threatening bacterial infections, and including the reactivation of granulomatous and fungal infections. More importantly, these agents are similar to steroids in blunting signs of infection, which may delay diagnosis and treatment.

The management of infection in patients on anti-TNF medications varies from case to case. In general, patients with a minor infection that does not require hospitalization or intravenous antibiotics can continue the biologic therapy while taking oral antibiotics. TNF inhibitors must be held in the event of a major infection.

Consultation with an infectious disease specialist is recommended, especially in complex cases.

Bacterial infections

An increased risk of minor bacterial infections such as urinary tract and respiratory infections has been well documented in several randomized control trials of anti-TNF agents, though other studies have shown no such increase in risk.^33,51–59

The threshold for using antibiotics for a suspected bacterial infection is somewhat shifted in favor of treatment in patients on anti-TNF therapy. The reason is twofold: as previously noted, infections may be worse than they appear, because anti-TNF drugs can mask the signs and symptoms of a serious infection, and in patients on these drugs, an untreated bacterial infection may rapidly become life-threatening.

In general, broad-spectrum antibiotics are not warranted unless the source of infection is unclear or the patient is in danger of hemodynamic compromise.

Opportunistic infections

The association of anti-TNF agents with opportunistic infections could be viewed as an extension of their normal and intended therapeutic activity as potent immunosuppressive agents.⁶⁸ Rheumatoid arthritis and inflammatory bowel disease are usually associated with conditions and situations that predispose patients to opportunistic infections, such as decreased immune response, malnutrition or malabsorption, surgeries, and concomitant immunosuppressive medications.⁷ Combination therapy with other immunosuppressive drugs and older age appear to markedly increase the risk of opportunistic infections, including mycobacterial and fungal infections, in patients with inflammatory bowel disease.⁷

Overall, opportunistic infections represent a measurable risk of anti-TNF therapy, and awareness and vigilance are important, especially in areas where opportunistic infections such as histoplasmosis and coccidiomycosis are endemic.⁵⁰ Furthermore, physicians must be aware of the higher risk of opportunistic infections when multiple immunosuppressive drugs are used concurrently.

Anti-TNF agents increase the risk of de novo granulomatous infections and of reactivating such infections. Granuloma formation and intracellular destruction of mycobacteria depend on TNF. TNF is important in maintaining the anatomic integrity of granulomas where these organisms have been sequestered, and blocking TNF leads to breakdown of granulomas and release of virulent organisms.^69,70

TNF inhibitors increase the risk of reactivation of latent tuberculosis infection. The risk is greater with infliximab and adalimumab than with etanercept,^71,72 and it has been described with certolizumab.⁷⁴ Study results are varied thus far but show a risk of tuberculosis reactivation five to 30 times higher than in the general population, with tremendous variability in risk depending on background rates of previous exposure.

The absence of typical tuberculosis symptoms further complicates care in these cases. Fever, weight loss, and night sweats tend to be TNF-mediated and are therefore masked by anti-TNF agents, leading to atypical presentations. In addition, active tuberculosis infection associated with TNF inhibitors is more likely to involve extrapulmonary sites such as the skin and musculoskeletal system and to be disseminated at presentation.

A paradoxical worsening of tuberculosis symptoms may also be seen in patients with latent tuberculosis reactivation, especially after discontinuing anti-TNF therapy. This is thought to result from an immune reconstitution inflammatory syndrome.

The pretreatment evaluation should include a history of risk factors, a physical examination, and either a tuberculin skin test or an interferon-gamma-release assay. Interferon-gamma-release assays are particularly helpful in patients who have received bacille Calmette-Guérin vaccination. In patients who test positive or have been exposed, tuberculosis treatment should begin 4 weeks before starting anti-TNF therapy, though the optimal timing of antituberculosis agents is still controversial.^74–77

If tuberculosis develops in a patient on anti-TNF therapy, he or she should receive antituberculosis drugs. Anti-TNF therapy should be stopped and should be resumed after 2 months only if no other treatment option is available.⁷⁵

Invasive opportunistic fungal infections

Invasive opportunistic fungal infections have been reported with anti-TNF therapy, including histoplasmosis and coccidioidomycosis.^78–80 Most patients who had histoplasmosis were treated with other immunosuppressive therapies and resided in or were raised near the Ohio or Mississippi River valleys, where this disease is endemic. Similarly, most cases of coccidioidomycosis were in endemic areas of Arizona, California, and Nevada, and patients on concomitant immunosuppressive therapy.⁷⁸

Currently, there is no evidence to recommend obtaining Histoplasma capsulatum or Coccidioides immitis serologies before initiating anti-TNF therapy in patients in endemic areas.⁸¹ However, patients must be instructed to seek medical attention quickly for pulmonary or febrile illnesses.

Viral hepatitis infections

The data on hepatitis B and hepatitis C in patients on biologic therapies are mostly limited to case reports.

Hepatitis B. A small prospective study from Spain followed the liver biochemistry tests and hepatitis B status of 80 patients with Crohn disease treated with infliximab. Of three patients who were chronic hepatitis B carriers before starting infliximab, two experienced reactivation of hepatitis B after discontinuing infliximab, and one ultimately died. The third patient was treated with lamivudine concurrently with infliximab without clinical or biochemical changes during or after therapy.⁸²

Similar findings were observed in two patients with rheumatoid arthritis on treatment with infliximab. One of the patients required liver transplantation, and both were treated with lamivudine, resulting in normalization of liver function test results.^83,84

Recent reviews indicate that despite these findings, hepatitis B reactivation after anti-TNF withdrawal may not be common.⁸⁵ There are limited data on hepatitis B reactivation and associated liver dysfunction in patients with inflammatory bowel disease treated with immunosuppressants. In a retrospective multicenter trial by Loras et al⁸⁶ in patients with inflammatory bowel disease who had viral hepatitis, 36% of patients positive for hepatitis B surface antigen developed liver dysfunction, and six patients developed liver failure. In that study, treatment with more than two immunosuppressants was an independent predictor of hepatitis B reactivation.

Prolonged immunosuppression (longer than 3 months) has also been identified as an independent predictor of liver dysfunction (OR 3.06; 95% 95% CI 1.02–9.16).⁸⁷

The European Association for the Study of the Liver and the American Association for the Study of Liver Diseases recommend starting lamivudine before chemotherapy or immunomodulator or immunosuppressive therapy in hepatitis B virus carriers and continuing preventive treatment for at least 6 months after stopping immunomodulating drugs. Lamivudine at a dose of 100 mg/day may reduce the risk of reactivation of hepatitis B.^88–90 Tenofovir and entecavir may be useful alternatives in patients with hepatitis B who have never received nucleoside analogues. Hepatitis B reactivation did not occur in any of the 16 patients who received preventive entecavir treatment while receiving immunosuppressive treatments.^89,91

In patients receiving immunosuppressive therapy, hepatitis B reactivation is associated with significant morbidity and mortality. Although risk factors for reactivation of hepatitis B virus infection have been identified, we recommend preventive treatment for all carriers positive for hepatitis B surface antigen. This should be done regardless of the number, type, and dosage of immunosuppressants and regardless of hepatitis B virus DNA levels.⁹⁰

The frequency of hepatitis B and hepatitis C infection in patients with Crohn disease has been reported to be as high as 24%. The high incidence is thought to be secondary to multiple blood transfusions and surgeries.⁹² The use of biologic agents, including anti-TNF agents, in chronic hepatitis B virus- or hepatitis C virus-infected patients can lead to enhanced viral replication and hepatitis exacerbation.

Although active viral replication can occur during treatment with biologic agents, reactivation or exacerbation can also occur after the anti-TNF agent is stopped.⁸² This finding has prompted the recommendation that all candidates for biologic therapy be tested for hepatitis B immunization status, followed by immunization in nonimmune patients before starting anti-TNF therapy.^93,94

Hepatitis C. There are no guidelines that adequately address the use of anti-TNF agents in patients with chronic hepatitis C infection.

Several small retrospective studies in rheumatoid arthritis patients with hepatitis C have shown that TNF inhibitors can be safely used without worsening liver function tests or changing the viral load.^95–98 This is reassuring and provides the subspecialist with another treatment option, as other therapies such as disease-modifying antirheumatic drugs and steroids are known to aggravate viral hepatitis and increase the risk of viremia.⁹⁶

Although small retrospective studies and one large randomized double-blind placebo-controlled trial have shown TNF inhibitors to be relatively safe in rheumatoid arthritis patients with hepatitis C, their use in these patients should be considered only with caution if they have evidence of hepatic synthetic dysfunction (eg, hypoalbuminemia, thrombocytopenia, increased international normalized ratio). The American College of Rheumatology recommends avoiding TNF inhibitors in Child-Pugh classes B and C.⁹⁹

PREGNANCY

Physicians caring for patients with rheumatoid arthritis and inflammatory bowel disease must be aware of how these diseases affect fecundity and fertility and how the medications can affect conception and pregnancy. Many patients have difficulty conceiving while their autoimmune disease is active, and better disease control may improve fecundity and result in unanticipated pregnancy. Patients should be advised of the need for contraception if pregnancy is ill-advised or undesired.

Many patients seek advice about teratogenicity before conceiving, or seek guidance about rheumatoid arthritis and inflammatory bowel disease treatment while pregnant.

Several studies have reported a higher risk of adverse pregnancy outcomes in patients with rheumatoid arthritis and inflammatory bowel disease than in the general population.^99–105 In inflammatory bowel disease, the odds of a premature delivery or having a low-birth-weight child are twice as high as in the normal population.^100,103 Higher rates of cesarean delivery and stillbirth have also been reported. The main predisposing factor appears to be the disease activity at the time of conception, as active disease seems to be linked to adverse pregnancy outcomes.

Treatment with anti-TNF agents may rapidly achieve and maintain remission, raising the question of the safety of continued anti-TNF use during pregnancy. The FDA classifies anti-TNF agents as category B drugs, as animal studies have not demonstrated fetal risk, and no well-controlled prospective study has yet been conducted with pregnant women.

In an observational study, Schnitzler et al¹⁰⁵ assessed the outcomes of 42 pregnancies in 35 patients with inflammatory bowel disease receiving either infliximab or adalimumab during pregnancy, compared with 56 pregnancies in 45 healthy patients without inflammatory bowel disease. There was no statistical difference in abortion rates between patients receiving anti-TNF agents and healthy women without inflammatory bowel disease (21% vs 14%, P = .4234). There was also no significant difference observed in birth weight, birth length, or cranial circumference of the children between the two groups. However, pregnancies with direct exposure to anti-TNF agents resulted in a higher frequency of premature delivery (25% vs 6%, P = .023).

Similar results were noted from the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool, or TREAT, registry, as well as from a large systematic review by Vinet et al¹⁰⁶ and case reports of rheumatoid arthritis and inflammatory bowel disease in women exposed to anti-TNF agents during pregnancy.

In addition, results from a recent systematic review of 38 studies of anti-TNF use and fetal risk, with a total of 437 women (189 on infliximab, 230 on adalimumab, 18 on certolizumab pegol), showed similar results.¹⁰⁷ In pregnancies exposed to anti-TNF agents, the rates of congenital abnormalities (3.4%), fetal deaths (8.5%), and preterm births (2.7%) were similar to those in the general population.

For patients in disease remission on TNF inhibitors, it is reasonable to continue these agents during pregnancy after careful discussion with the patient. Fetal safety and infant immunization response after delivery are the primary concerns in these cases.

Both infliximab and adalimumab cross the placenta and remain detectable in the baby’s circulation 4 months (for adalimumab) to 6 months (for infliximab) after delivery. It is currently recommended that infliximab be stopped at 32 weeks of gestation for the remainder of the pregnancy and that adalimumab be stopped at 34 to 36 weeks, given a planned 40-week gestation.

Certolizumab does not cross the placenta in significant amounts and should be continued throughout pregnancy; drug levels in infants were shown to be less than 2 μg/mL, even when dosed the week of delivery.^108–112

TAKE-HOME POINTS

• All health care providers of patients with rheumatoid arthritis and inflammatory bowel disease should be familiar with anti-TNF agents used in treating these diseases.
• The benefits of controlling the disease far outweigh the risks of therapy when used appropriately.
• Care of these patients should be multidisciplinary, with clear communication between primary care physician and specialist.
• Patient education and monitoring combined with prompt communication between primary care physician and specialist are key.

Biologic agents such as those that block tumor necrosis factor (TNF) alpha have revolutionized the treatment of autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease, dramatically improving disease control and quality of life. In addition, they have made true disease remission possible in some cases.

However, as with any new therapy, a variety of side effects must be considered.

WHAT ARE BIOLOGIC AGENTS?

Biologic agents are genetically engineered drugs manufactured or synthesized in vitro from molecules such as proteins, genes, and antibodies present in living organisms. By targeting specific molecular components of the inflammatory cascade, including cytokines, these drugs alter certain aspects of the body’s inflammatory response in autoimmune diseases. Because TNF inhibitors are the most widely used biologic agents in the United States, this review will focus on them.

TNF INHIBITORS

TNF inhibitors suppress the inflammatory cascade by inactivating TNF alpha, a cytokine that promotes inflammation in the intestine, synovial tissue, and other sites.^1,2

Several TNF inhibitors are available. Etanercept and infliximab were the first two to receive US Food and Drug Administration (FDA) approval, and they are extensively used. Etanercept, a soluble TNF receptor given subcutaneously, was approved for treating rheumatoid arthritis in 1998. Infliximab, a chimeric monoclonal antibody (75% human and 25% mouse protein sequence) given intravenously, received FDA approval for treating Crohn disease in 1998 and for rheumatoid arthritis in 1999. Other anti-TNF agents with varying properties are also available.

Table 1 lists anti-TNF agents approved for treating rheumatoid arthritis and inflammatory bowel disease. These are chronic, relapsing diseases that significantly and dramatically reduce quality of life, especially when they are poorly controlled.^3,4 Untreated disease has been associated with malignancy, infection, pregnancy loss, and malnutrition.^5–8 TNF inhibitors are aimed at patients who have moderate to severe disease or for whom previous treatments have failed, to help them achieve and maintain steroid-free remission. However, use of these agents is tempered by the risk of potentially serious side effects.

Special thought should also be given to the direct costs of the drugs (up to $30,000 per year, not counting the cost of their administration) and to the indirect costs such as time away from work to receive treatment. These are major considerations in some cases, and patients should be selected carefully for treatment with these drugs.

BEFORE STARTING THERAPY

Before starting anti-TNF therapy, several steps can reduce the risk of serious adverse events.

Take a focused history

The clinical history should include inquiries about previous bacterial, fungal, and tuberculosis infections or exposure; diabetes; and other immunocompromised states that increase the risk of acquiring potentially life-threatening infections.

Details of particular geographic areas of residence, occupational exposures, and social history should be sought. These include history of incarceration (which may put patients at risk of tuberculosis) and residence in the Ohio River valley or in the southwestern or midwestern United States (which may increase the risk of histoplasmosis, coccidioidomycosis, and other fungal infections).

Bring vaccinations up to date

Age-appropriate vaccinations should be discussed and given, ideally before starting therapy. These include influenza vaccine every year and tetanus boosters every 10 years for all and, as appropriate, varicella, human papillomavirus, and pneumococcal vaccinations. The US Centers for Disease Control and Prevention recommend an additional dose of the pneumococcal vaccine if more than 5 years have elapsed since the first one, and many clinicians opt to give it every 5 years.

In general, live-attenuated vaccines, including the intranasal influenza vaccine, are contraindicated in patients taking biologic agents.⁹ For patients at high risk of exposure or infection, it may be reasonable to hold the biologic agent for a period of time, vaccinate, and resume the biologic agent a month later.

Recent data suggest that the varicella zoster vaccine may be safely given to older patients with immune-mediated diseases such as rheumatoid arthritis and inflammatory bowel disease taking biologic agents.¹⁰ New guidelines from the American College of Rheumatology recommend age-appropriate vaccines for rheumatoid arthritis patients age 60 and older before biologic treatments are started. Case-by-case discussion with the subspecialist and the patient is recommended.

Screen for chronic infections

Tuberculosis screening with a purified protein derivative test or an interferon-gamma-release (Quantiferon) assay followed by chest radiography in patients with a positive test is mandatory before giving a TNF inhibitor.

Hepatitis B virus status should be determined before starting anti-TNF therapy.¹¹

Hepatitis B vaccination has been recommended for patients with inflammatory bowel disease, but no clear recommendation exists for patients with rheumatic disease. Patients with inflammatory bowel disease tend to have low rates of response to hepatitis B vaccination^12,13; possible reasons include their lack of an appropriate innate immune response to infectious agents, malnutrition, surgery, older age, and immunosuppressive drugs.¹⁴ An accelerated vaccination protocol with recombinant hepatitis B vaccine (Energix-B) in a double dose at 0, 1, and 2 months has been shown to improve response rates.¹⁵

Whenever possible, it may be better to vaccinate patients before starting immunosuppressive therapy, and to check postvaccination titers to ensure adequate response.

A full physical examination with special attention to skin rashes should be performed. This may serve as a baseline to assist early detection of new rashes associated with anti-TNF therapy.

A baseline complete blood cell count and complete metabolic panel should be routinely obtained before starting therapy (and thereafter at the discretion of the physician). In conjunction with follow-up tests, they can help detect an unexpected decrease in white blood cell count or abnormal results on the liver panel.¹⁶ These baseline and follow-up tests are generally performed by the subspecialist, and the results are shared with the primary care physician.

Table 2 summarizes key information to be sought before starting a patient on a TNF inhibitor.

ADVERSE EFFECTS OF ANTI-TNF DRUGS

Infusion reactions, infections, cardiac arrhythmias, demyelinating disorders, skin infections, and malignancies have been reported with anti-TNF therapy. The relative frequencies of these adverse events are summarized in Table 3.^17–22

NONINFECTIOUS COMPLICATIONS OF TNF INHIBITORS

Injection site reactions

When anti-TNF agents are given subcutaneously, injection site reactions are common (occurring in up to 40% of patients) and are considered minor.¹¹ Reactions, including significant pain, typically occur within the first few months of therapy. They can last 2 to 5 days but rarely warrant stopping therapy. Treatment with ice and an antihistamine is almost always sufficient to control symptoms.

Infusion reactions with infliximab

Infliximab can cause both acute and delayed infusion reactions. Acute reactions can occur up to 24 hours after infusion but usually appear within 10 minutes of administration and are handled by the infusion suite staff. They range from the severe immunoglobulin E-mediated type I reaction, manifesting with hypotension, bronchospasm, and urticaria, to the milder anaphylactoid-type reaction, which constitutes the majority.^23–25

While most primary care physicians will not encounter an acute reaction, family doctors and emergency room physicians may encounter delayed reactions, which can develop 1 to 14 days after infusion. These reactions usually resemble serum sickness and present with joint pain, fatigue, myalgia, and fever. But, unlike classic serum sickness, these reactions are generally not associated with a rash.

With nonspecific symptoms, the diagnosis may be easy to overlook. However, establishing this diagnosis is important because repeat therapy may result in a more severe reaction upon reexposure to the drug.

Once diagnosed, these reactions can be treated symptomatically with a combination of acetaminophen and diphenhydramine after discussion between the primary care physician and subspecialist.^23,24

Autoimmune syndromes

Several studies have reported a small percentage of patients treated with anti-TNF agents who develop paradoxical autoimmune conditions. These range from asymptomatic immunologic alterations, including the formation of antinuclear antibodies and antibodies to double-stranded DNA, to life-threatening systemic autoimmune diseases.^26,27

Autoimmune diseases associated with anti-TNF treatment include a lupus-like syndrome, vasculitides, and psoriatic skin lesions. These syndromes warrant stopping the inciting drug and, on occasion, giving corticosteroids. Most cases arise between 1 month and 1 year of starting treatment, and almost 75% resolve completely after the anti-TNF therapy is stopped.²⁶

Interestingly, anti-TNF agents are approved for treating psoriasis and psoriatic arthritis, but psoriasis has paradoxically developed in patients being treated with these drugs for other autoimmune diseases. The FDA has reviewed 69 cases of new-onset psoriasis with anti-TNF therapy, including 17 pustular and 15 palmoplantar cases. The 12 most severe cases resulted in hospitalization, and symptoms resolved in most after treatment cessation.²⁸

Fiorino et al²⁹ counted 18 reported cases of psoriasis induced by anti-TNF therapy in patients with inflammatory bowel disease and concluded that it is rare. Harrison et al³⁰ reported similar findings in patients with rheumatoid arthritis, with an increased incidence rate of 1.04 per 1,000 person-years. New-onset psoriasis was most common in patients treated with adalimumab. An example of the rash is seen in Figure 1.

CARDIOVASCULAR SIDE EFFECTS

Cardiovascular side effects of anti-TNF agents range from nonspecific and asymptomatic arrhythmias to worsening of heart failure.

Circulating levels of TNF are increased in patients with heart failure, and studies have evaluated the effects of TNF inhibition with infliximab on cardiac function and overall survival.^31,32 The combined risk of death from any cause or hospitalization from heart failure was significantly higher in the infliximab groups, and the effects persisted for up to 5 months after stopping therapy.

Other studies^22,33 have evaluated the effects of infliximab and etanercept on cardiac function and overall survival. Results showed possible exacerbation of heart failure with etanercept and increased risk of death with infliximab in patients with New York Heart Association (NYHA) class III or IV heart failure and left ventricular ejection fractions less than 35%.

Case reports have also described patients with worsening or new-onset heart failure on TNF inhibitors, including patients younger than 50 years and without identifiable cardiovascular risk factors.

Data analyses^31,34,35 from large clinical registries have reported no significant increase in heart failure attributable to TNF inhibitors. However, we have concerns about the methodology of these analyses.

Currently, anti-TNF therapy is contraindicated in patients with NYHA class III or IV heart failure. Data are inconclusive for patients with class I or II heart failure. Baseline echocardiography and cardiology consultation can be considered, with close monitoring and avoidance of high doses of TNF inhibitors. If heart failure develops in a patient on anti-TNF therapy, the drug should be discontinued and the patient should be evaluated further.³⁶

DEMYELINATING DISEASE, INCLUDING MULTIPLE SCLEROSIS

Anti-TNF agents have been associated with the onset or exacerbation of clinical symptoms and radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis.^37–40 Mohan et al³⁸ identified 19 cases of demyelinating events occurring after administration of anti-TNF agents in early 2001. In most cases, symptoms improved or resolved after therapy was stopped.

Optic neuritis,^41,42 bilateral optic neuropathy,⁴³ and aseptic meningitis⁴⁴ have also been reported, but these have occurred only rarely.

How common are these effects? Postmarketing surveillance in patients with rheumatoid arthritis yields an estimated incidence of demyelinating disorders of 1 per 1,000 patient-years with adalimumab therapy.⁴⁵ Complicating the assessment is an observed slight increase in risk of demyelinating conditions associated with inflammatory bowel disease.

Symptoms that should heighten the physician’s suspicion of this adverse effect include confusion, paresthesias, and ataxia. Patients on anti-TNF therapy who develop new visual symptoms should be checked for painless visual loss as a sign of early demyelinating disease.

Although data that conclusively link anti-TNF agents to multiple sclerosis are lacking, these drugs should not be initiated in patients who have a history of demyelinating disease, and treatment should be stopped promptly if the diagnosis is suspected.

MALIGNANCY

Whether anti-TNF therapy is directly linked to development of malignancies is difficult to determine. There are many confounding factors, including the risk of malignancy in underlying inflammatory disease and the concomitant use of other medications such as thiopurines, which have a known association with lymphoma.⁴⁶

The incidence of lymphoma is twice as high in rheumatoid arthritis patients as in the general population.⁴⁷ The risk is higher in those with more aggressive joint disease—the subset of rheumatoid arthritis patients who are more likely to be given anti-TNF agents.⁵

In patients with inflammatory bowel disease, the risk of cholangiocarcinoma is four times higher, and the risk of small-bowel adenocarcinoma is 16 to 18 times higher, but no increased risk of lymphoma has been identified in this population.^48,49

Data from six clinical trials of infliximab, including a long-term study of its safety in Crohn disease, suggest it poses no increase in overall risk of malignancy.^50–52 Similar results have been reported in patients with other rheumatic diseases.⁸ Information on this topic is constantly evolving, and studies range from case series to clinical trials to large patient registries.

The decision to use a TNF inhibitor should be based on the patient’s clinical picture and risk factors. Discussion of the risks and benefits of therapy with the patient should be clearly documented.

Non-Hodgkin lymphoma

Evidence about the risk of lymphoma with anti-TNF use is mixed, as up to two-thirds of patients on anti-TNF therapy have received concomitant nonbiologic immunosuppressive medications, making it difficult to determine the true risk from the biologic agents alone.⁵³ Current evidence both supports^9,53–56 and refutes^7,55,57–60 the idea that anti-TNF agents increase lymphoma risk.

In patients with inflammatory bowel disease, several population-based studies have not shown a clear increase in lymphoma risk with anti-TNF use.^56,59,60 Pedersen et al,⁶¹ in a meta-analysis of eight studies, confirmed these findings by showing no overall lymphoma risk in patients with inflammatory bowel disease.

However, a Canadian population-based study found a statistically significant increase in non-Hodgkin lymphoma in males with Crohn disease, with an incidence ratio of 3.63 (95% confidence interval [CI] 1.53–8.62).⁶¹ Additionally, Siegel et al⁶² found a significantly higher risk (6.1 cases per 10,000 patients) in patients treated with anti-TNF agents and thiopurines than in the general population (1.9 cases per 10,000 people). Although the difference was statistically significant, the overall risk is still very low.

Patients with rheumatoid arthritis seem to have a risk of lymphoma two to three times higher than in the general population. However, large population-based studies have not shown a statistically significant increase in the risk of lymphoma with anti-TNF therapy.⁶³

Hepatosplenic T-cell lymphoma is a rare subtype of peripheral T-cell non-Hodgkin lymphoma; 25 cases have been reported in patients receiving anti-TNF therapy.⁶⁴ Although the risk is extremely low (< 0.05%), physicians must carefully consider the risks and benefits of combination therapy, especially in young male patients with inflammatory bowel disease, since death is the usual outcome of this disease.^65–67

Skin cancers

Wolfe and Michaud⁸ evaluated malignancy risk in rheumatoid arthritis patients being treated with biologic agents, including TNF inhibitors, using a large longitudinal database. These data were compared with those of the US Surveillance, Epidemiology, and End-Results (SEER) national database. No increase in the overall cancer rate was seen in rheumatoid arthritis patients (standardized incidence ratio [SIR] 1.0, 95% CI 1.0–1.1).

However, melanoma was more common in rheumatoid arthritis patients compared with SEER rates (SIR 1.7, 95% CI 1.3–2.3).⁸ In addition, biologic therapy was associated with a higher (but not statistically significant) risk of melanoma (odds ratio [OR] 2.3, 95% CI 0.9–5.4) and a higher risk of nonmelanoma skin cancer (OR 1.5, 95% CI 1.2–1.8), but not of other types of cancer.⁸

INFECTION

Patients on anti-TNF therapy are at a higher risk of infection, ranging from minor to life-threatening bacterial infections, and including the reactivation of granulomatous and fungal infections. More importantly, these agents are similar to steroids in blunting signs of infection, which may delay diagnosis and treatment.

The management of infection in patients on anti-TNF medications varies from case to case. In general, patients with a minor infection that does not require hospitalization or intravenous antibiotics can continue the biologic therapy while taking oral antibiotics. TNF inhibitors must be held in the event of a major infection.

Consultation with an infectious disease specialist is recommended, especially in complex cases.

Bacterial infections

An increased risk of minor bacterial infections such as urinary tract and respiratory infections has been well documented in several randomized control trials of anti-TNF agents, though other studies have shown no such increase in risk.^33,51–59

The threshold for using antibiotics for a suspected bacterial infection is somewhat shifted in favor of treatment in patients on anti-TNF therapy. The reason is twofold: as previously noted, infections may be worse than they appear, because anti-TNF drugs can mask the signs and symptoms of a serious infection, and in patients on these drugs, an untreated bacterial infection may rapidly become life-threatening.

In general, broad-spectrum antibiotics are not warranted unless the source of infection is unclear or the patient is in danger of hemodynamic compromise.

Opportunistic infections

The association of anti-TNF agents with opportunistic infections could be viewed as an extension of their normal and intended therapeutic activity as potent immunosuppressive agents.⁶⁸ Rheumatoid arthritis and inflammatory bowel disease are usually associated with conditions and situations that predispose patients to opportunistic infections, such as decreased immune response, malnutrition or malabsorption, surgeries, and concomitant immunosuppressive medications.⁷ Combination therapy with other immunosuppressive drugs and older age appear to markedly increase the risk of opportunistic infections, including mycobacterial and fungal infections, in patients with inflammatory bowel disease.⁷

Overall, opportunistic infections represent a measurable risk of anti-TNF therapy, and awareness and vigilance are important, especially in areas where opportunistic infections such as histoplasmosis and coccidiomycosis are endemic.⁵⁰ Furthermore, physicians must be aware of the higher risk of opportunistic infections when multiple immunosuppressive drugs are used concurrently.

Anti-TNF agents increase the risk of de novo granulomatous infections and of reactivating such infections. Granuloma formation and intracellular destruction of mycobacteria depend on TNF. TNF is important in maintaining the anatomic integrity of granulomas where these organisms have been sequestered, and blocking TNF leads to breakdown of granulomas and release of virulent organisms.^69,70

TNF inhibitors increase the risk of reactivation of latent tuberculosis infection. The risk is greater with infliximab and adalimumab than with etanercept,^71,72 and it has been described with certolizumab.⁷⁴ Study results are varied thus far but show a risk of tuberculosis reactivation five to 30 times higher than in the general population, with tremendous variability in risk depending on background rates of previous exposure.

The absence of typical tuberculosis symptoms further complicates care in these cases. Fever, weight loss, and night sweats tend to be TNF-mediated and are therefore masked by anti-TNF agents, leading to atypical presentations. In addition, active tuberculosis infection associated with TNF inhibitors is more likely to involve extrapulmonary sites such as the skin and musculoskeletal system and to be disseminated at presentation.

A paradoxical worsening of tuberculosis symptoms may also be seen in patients with latent tuberculosis reactivation, especially after discontinuing anti-TNF therapy. This is thought to result from an immune reconstitution inflammatory syndrome.

The pretreatment evaluation should include a history of risk factors, a physical examination, and either a tuberculin skin test or an interferon-gamma-release assay. Interferon-gamma-release assays are particularly helpful in patients who have received bacille Calmette-Guérin vaccination. In patients who test positive or have been exposed, tuberculosis treatment should begin 4 weeks before starting anti-TNF therapy, though the optimal timing of antituberculosis agents is still controversial.^74–77

If tuberculosis develops in a patient on anti-TNF therapy, he or she should receive antituberculosis drugs. Anti-TNF therapy should be stopped and should be resumed after 2 months only if no other treatment option is available.⁷⁵

Invasive opportunistic fungal infections

Invasive opportunistic fungal infections have been reported with anti-TNF therapy, including histoplasmosis and coccidioidomycosis.^78–80 Most patients who had histoplasmosis were treated with other immunosuppressive therapies and resided in or were raised near the Ohio or Mississippi River valleys, where this disease is endemic. Similarly, most cases of coccidioidomycosis were in endemic areas of Arizona, California, and Nevada, and patients on concomitant immunosuppressive therapy.⁷⁸

Currently, there is no evidence to recommend obtaining Histoplasma capsulatum or Coccidioides immitis serologies before initiating anti-TNF therapy in patients in endemic areas.⁸¹ However, patients must be instructed to seek medical attention quickly for pulmonary or febrile illnesses.

Viral hepatitis infections

The data on hepatitis B and hepatitis C in patients on biologic therapies are mostly limited to case reports.

Hepatitis B. A small prospective study from Spain followed the liver biochemistry tests and hepatitis B status of 80 patients with Crohn disease treated with infliximab. Of three patients who were chronic hepatitis B carriers before starting infliximab, two experienced reactivation of hepatitis B after discontinuing infliximab, and one ultimately died. The third patient was treated with lamivudine concurrently with infliximab without clinical or biochemical changes during or after therapy.⁸²

Similar findings were observed in two patients with rheumatoid arthritis on treatment with infliximab. One of the patients required liver transplantation, and both were treated with lamivudine, resulting in normalization of liver function test results.^83,84

Recent reviews indicate that despite these findings, hepatitis B reactivation after anti-TNF withdrawal may not be common.⁸⁵ There are limited data on hepatitis B reactivation and associated liver dysfunction in patients with inflammatory bowel disease treated with immunosuppressants. In a retrospective multicenter trial by Loras et al⁸⁶ in patients with inflammatory bowel disease who had viral hepatitis, 36% of patients positive for hepatitis B surface antigen developed liver dysfunction, and six patients developed liver failure. In that study, treatment with more than two immunosuppressants was an independent predictor of hepatitis B reactivation.

Prolonged immunosuppression (longer than 3 months) has also been identified as an independent predictor of liver dysfunction (OR 3.06; 95% 95% CI 1.02–9.16).⁸⁷

The European Association for the Study of the Liver and the American Association for the Study of Liver Diseases recommend starting lamivudine before chemotherapy or immunomodulator or immunosuppressive therapy in hepatitis B virus carriers and continuing preventive treatment for at least 6 months after stopping immunomodulating drugs. Lamivudine at a dose of 100 mg/day may reduce the risk of reactivation of hepatitis B.^88–90 Tenofovir and entecavir may be useful alternatives in patients with hepatitis B who have never received nucleoside analogues. Hepatitis B reactivation did not occur in any of the 16 patients who received preventive entecavir treatment while receiving immunosuppressive treatments.^89,91

In patients receiving immunosuppressive therapy, hepatitis B reactivation is associated with significant morbidity and mortality. Although risk factors for reactivation of hepatitis B virus infection have been identified, we recommend preventive treatment for all carriers positive for hepatitis B surface antigen. This should be done regardless of the number, type, and dosage of immunosuppressants and regardless of hepatitis B virus DNA levels.⁹⁰

The frequency of hepatitis B and hepatitis C infection in patients with Crohn disease has been reported to be as high as 24%. The high incidence is thought to be secondary to multiple blood transfusions and surgeries.⁹² The use of biologic agents, including anti-TNF agents, in chronic hepatitis B virus- or hepatitis C virus-infected patients can lead to enhanced viral replication and hepatitis exacerbation.

Although active viral replication can occur during treatment with biologic agents, reactivation or exacerbation can also occur after the anti-TNF agent is stopped.⁸² This finding has prompted the recommendation that all candidates for biologic therapy be tested for hepatitis B immunization status, followed by immunization in nonimmune patients before starting anti-TNF therapy.^93,94

Hepatitis C. There are no guidelines that adequately address the use of anti-TNF agents in patients with chronic hepatitis C infection.

Several small retrospective studies in rheumatoid arthritis patients with hepatitis C have shown that TNF inhibitors can be safely used without worsening liver function tests or changing the viral load.^95–98 This is reassuring and provides the subspecialist with another treatment option, as other therapies such as disease-modifying antirheumatic drugs and steroids are known to aggravate viral hepatitis and increase the risk of viremia.⁹⁶

Although small retrospective studies and one large randomized double-blind placebo-controlled trial have shown TNF inhibitors to be relatively safe in rheumatoid arthritis patients with hepatitis C, their use in these patients should be considered only with caution if they have evidence of hepatic synthetic dysfunction (eg, hypoalbuminemia, thrombocytopenia, increased international normalized ratio). The American College of Rheumatology recommends avoiding TNF inhibitors in Child-Pugh classes B and C.⁹⁹

PREGNANCY

Physicians caring for patients with rheumatoid arthritis and inflammatory bowel disease must be aware of how these diseases affect fecundity and fertility and how the medications can affect conception and pregnancy. Many patients have difficulty conceiving while their autoimmune disease is active, and better disease control may improve fecundity and result in unanticipated pregnancy. Patients should be advised of the need for contraception if pregnancy is ill-advised or undesired.

Many patients seek advice about teratogenicity before conceiving, or seek guidance about rheumatoid arthritis and inflammatory bowel disease treatment while pregnant.

Several studies have reported a higher risk of adverse pregnancy outcomes in patients with rheumatoid arthritis and inflammatory bowel disease than in the general population.^99–105 In inflammatory bowel disease, the odds of a premature delivery or having a low-birth-weight child are twice as high as in the normal population.^100,103 Higher rates of cesarean delivery and stillbirth have also been reported. The main predisposing factor appears to be the disease activity at the time of conception, as active disease seems to be linked to adverse pregnancy outcomes.

Treatment with anti-TNF agents may rapidly achieve and maintain remission, raising the question of the safety of continued anti-TNF use during pregnancy. The FDA classifies anti-TNF agents as category B drugs, as animal studies have not demonstrated fetal risk, and no well-controlled prospective study has yet been conducted with pregnant women.

In an observational study, Schnitzler et al¹⁰⁵ assessed the outcomes of 42 pregnancies in 35 patients with inflammatory bowel disease receiving either infliximab or adalimumab during pregnancy, compared with 56 pregnancies in 45 healthy patients without inflammatory bowel disease. There was no statistical difference in abortion rates between patients receiving anti-TNF agents and healthy women without inflammatory bowel disease (21% vs 14%, P = .4234). There was also no significant difference observed in birth weight, birth length, or cranial circumference of the children between the two groups. However, pregnancies with direct exposure to anti-TNF agents resulted in a higher frequency of premature delivery (25% vs 6%, P = .023).

Similar results were noted from the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool, or TREAT, registry, as well as from a large systematic review by Vinet et al¹⁰⁶ and case reports of rheumatoid arthritis and inflammatory bowel disease in women exposed to anti-TNF agents during pregnancy.

In addition, results from a recent systematic review of 38 studies of anti-TNF use and fetal risk, with a total of 437 women (189 on infliximab, 230 on adalimumab, 18 on certolizumab pegol), showed similar results.¹⁰⁷ In pregnancies exposed to anti-TNF agents, the rates of congenital abnormalities (3.4%), fetal deaths (8.5%), and preterm births (2.7%) were similar to those in the general population.

For patients in disease remission on TNF inhibitors, it is reasonable to continue these agents during pregnancy after careful discussion with the patient. Fetal safety and infant immunization response after delivery are the primary concerns in these cases.

Both infliximab and adalimumab cross the placenta and remain detectable in the baby’s circulation 4 months (for adalimumab) to 6 months (for infliximab) after delivery. It is currently recommended that infliximab be stopped at 32 weeks of gestation for the remainder of the pregnancy and that adalimumab be stopped at 34 to 36 weeks, given a planned 40-week gestation.

Certolizumab does not cross the placenta in significant amounts and should be continued throughout pregnancy; drug levels in infants were shown to be less than 2 μg/mL, even when dosed the week of delivery.^108–112

TAKE-HOME POINTS

• All health care providers of patients with rheumatoid arthritis and inflammatory bowel disease should be familiar with anti-TNF agents used in treating these diseases.
• The benefits of controlling the disease far outweigh the risks of therapy when used appropriately.
• Care of these patients should be multidisciplinary, with clear communication between primary care physician and specialist.
• Patient education and monitoring combined with prompt communication between primary care physician and specialist are key.

Biologic agents such as those that block tumor necrosis factor (TNF) alpha have revolutionized the treatment of autoimmune diseases like rheumatoid arthritis and inflammatory bowel disease, dramatically improving disease control and quality of life. In addition, they have made true disease remission possible in some cases.

However, as with any new therapy, a variety of side effects must be considered.

WHAT ARE BIOLOGIC AGENTS?

Biologic agents are genetically engineered drugs manufactured or synthesized in vitro from molecules such as proteins, genes, and antibodies present in living organisms. By targeting specific molecular components of the inflammatory cascade, including cytokines, these drugs alter certain aspects of the body’s inflammatory response in autoimmune diseases. Because TNF inhibitors are the most widely used biologic agents in the United States, this review will focus on them.

TNF INHIBITORS

TNF inhibitors suppress the inflammatory cascade by inactivating TNF alpha, a cytokine that promotes inflammation in the intestine, synovial tissue, and other sites.^1,2

Several TNF inhibitors are available. Etanercept and infliximab were the first two to receive US Food and Drug Administration (FDA) approval, and they are extensively used. Etanercept, a soluble TNF receptor given subcutaneously, was approved for treating rheumatoid arthritis in 1998. Infliximab, a chimeric monoclonal antibody (75% human and 25% mouse protein sequence) given intravenously, received FDA approval for treating Crohn disease in 1998 and for rheumatoid arthritis in 1999. Other anti-TNF agents with varying properties are also available.

Table 1 lists anti-TNF agents approved for treating rheumatoid arthritis and inflammatory bowel disease. These are chronic, relapsing diseases that significantly and dramatically reduce quality of life, especially when they are poorly controlled.^3,4 Untreated disease has been associated with malignancy, infection, pregnancy loss, and malnutrition.^5–8 TNF inhibitors are aimed at patients who have moderate to severe disease or for whom previous treatments have failed, to help them achieve and maintain steroid-free remission. However, use of these agents is tempered by the risk of potentially serious side effects.

Special thought should also be given to the direct costs of the drugs (up to $30,000 per year, not counting the cost of their administration) and to the indirect costs such as time away from work to receive treatment. These are major considerations in some cases, and patients should be selected carefully for treatment with these drugs.

BEFORE STARTING THERAPY

Before starting anti-TNF therapy, several steps can reduce the risk of serious adverse events.

Take a focused history

The clinical history should include inquiries about previous bacterial, fungal, and tuberculosis infections or exposure; diabetes; and other immunocompromised states that increase the risk of acquiring potentially life-threatening infections.

Details of particular geographic areas of residence, occupational exposures, and social history should be sought. These include history of incarceration (which may put patients at risk of tuberculosis) and residence in the Ohio River valley or in the southwestern or midwestern United States (which may increase the risk of histoplasmosis, coccidioidomycosis, and other fungal infections).

Bring vaccinations up to date

Age-appropriate vaccinations should be discussed and given, ideally before starting therapy. These include influenza vaccine every year and tetanus boosters every 10 years for all and, as appropriate, varicella, human papillomavirus, and pneumococcal vaccinations. The US Centers for Disease Control and Prevention recommend an additional dose of the pneumococcal vaccine if more than 5 years have elapsed since the first one, and many clinicians opt to give it every 5 years.

In general, live-attenuated vaccines, including the intranasal influenza vaccine, are contraindicated in patients taking biologic agents.⁹ For patients at high risk of exposure or infection, it may be reasonable to hold the biologic agent for a period of time, vaccinate, and resume the biologic agent a month later.

Recent data suggest that the varicella zoster vaccine may be safely given to older patients with immune-mediated diseases such as rheumatoid arthritis and inflammatory bowel disease taking biologic agents.¹⁰ New guidelines from the American College of Rheumatology recommend age-appropriate vaccines for rheumatoid arthritis patients age 60 and older before biologic treatments are started. Case-by-case discussion with the subspecialist and the patient is recommended.

Screen for chronic infections

Tuberculosis screening with a purified protein derivative test or an interferon-gamma-release (Quantiferon) assay followed by chest radiography in patients with a positive test is mandatory before giving a TNF inhibitor.

Hepatitis B virus status should be determined before starting anti-TNF therapy.¹¹

Hepatitis B vaccination has been recommended for patients with inflammatory bowel disease, but no clear recommendation exists for patients with rheumatic disease. Patients with inflammatory bowel disease tend to have low rates of response to hepatitis B vaccination^12,13; possible reasons include their lack of an appropriate innate immune response to infectious agents, malnutrition, surgery, older age, and immunosuppressive drugs.¹⁴ An accelerated vaccination protocol with recombinant hepatitis B vaccine (Energix-B) in a double dose at 0, 1, and 2 months has been shown to improve response rates.¹⁵

Whenever possible, it may be better to vaccinate patients before starting immunosuppressive therapy, and to check postvaccination titers to ensure adequate response.

A full physical examination with special attention to skin rashes should be performed. This may serve as a baseline to assist early detection of new rashes associated with anti-TNF therapy.

A baseline complete blood cell count and complete metabolic panel should be routinely obtained before starting therapy (and thereafter at the discretion of the physician). In conjunction with follow-up tests, they can help detect an unexpected decrease in white blood cell count or abnormal results on the liver panel.¹⁶ These baseline and follow-up tests are generally performed by the subspecialist, and the results are shared with the primary care physician.

Table 2 summarizes key information to be sought before starting a patient on a TNF inhibitor.

ADVERSE EFFECTS OF ANTI-TNF DRUGS

Infusion reactions, infections, cardiac arrhythmias, demyelinating disorders, skin infections, and malignancies have been reported with anti-TNF therapy. The relative frequencies of these adverse events are summarized in Table 3.^17–22

NONINFECTIOUS COMPLICATIONS OF TNF INHIBITORS

Injection site reactions

When anti-TNF agents are given subcutaneously, injection site reactions are common (occurring in up to 40% of patients) and are considered minor.¹¹ Reactions, including significant pain, typically occur within the first few months of therapy. They can last 2 to 5 days but rarely warrant stopping therapy. Treatment with ice and an antihistamine is almost always sufficient to control symptoms.

Infusion reactions with infliximab

Infliximab can cause both acute and delayed infusion reactions. Acute reactions can occur up to 24 hours after infusion but usually appear within 10 minutes of administration and are handled by the infusion suite staff. They range from the severe immunoglobulin E-mediated type I reaction, manifesting with hypotension, bronchospasm, and urticaria, to the milder anaphylactoid-type reaction, which constitutes the majority.^23–25

While most primary care physicians will not encounter an acute reaction, family doctors and emergency room physicians may encounter delayed reactions, which can develop 1 to 14 days after infusion. These reactions usually resemble serum sickness and present with joint pain, fatigue, myalgia, and fever. But, unlike classic serum sickness, these reactions are generally not associated with a rash.

With nonspecific symptoms, the diagnosis may be easy to overlook. However, establishing this diagnosis is important because repeat therapy may result in a more severe reaction upon reexposure to the drug.

Once diagnosed, these reactions can be treated symptomatically with a combination of acetaminophen and diphenhydramine after discussion between the primary care physician and subspecialist.^23,24

Autoimmune syndromes

Several studies have reported a small percentage of patients treated with anti-TNF agents who develop paradoxical autoimmune conditions. These range from asymptomatic immunologic alterations, including the formation of antinuclear antibodies and antibodies to double-stranded DNA, to life-threatening systemic autoimmune diseases.^26,27

Autoimmune diseases associated with anti-TNF treatment include a lupus-like syndrome, vasculitides, and psoriatic skin lesions. These syndromes warrant stopping the inciting drug and, on occasion, giving corticosteroids. Most cases arise between 1 month and 1 year of starting treatment, and almost 75% resolve completely after the anti-TNF therapy is stopped.²⁶

Interestingly, anti-TNF agents are approved for treating psoriasis and psoriatic arthritis, but psoriasis has paradoxically developed in patients being treated with these drugs for other autoimmune diseases. The FDA has reviewed 69 cases of new-onset psoriasis with anti-TNF therapy, including 17 pustular and 15 palmoplantar cases. The 12 most severe cases resulted in hospitalization, and symptoms resolved in most after treatment cessation.²⁸

Fiorino et al²⁹ counted 18 reported cases of psoriasis induced by anti-TNF therapy in patients with inflammatory bowel disease and concluded that it is rare. Harrison et al³⁰ reported similar findings in patients with rheumatoid arthritis, with an increased incidence rate of 1.04 per 1,000 person-years. New-onset psoriasis was most common in patients treated with adalimumab. An example of the rash is seen in Figure 1.

CARDIOVASCULAR SIDE EFFECTS

Cardiovascular side effects of anti-TNF agents range from nonspecific and asymptomatic arrhythmias to worsening of heart failure.

Circulating levels of TNF are increased in patients with heart failure, and studies have evaluated the effects of TNF inhibition with infliximab on cardiac function and overall survival.^31,32 The combined risk of death from any cause or hospitalization from heart failure was significantly higher in the infliximab groups, and the effects persisted for up to 5 months after stopping therapy.

Other studies^22,33 have evaluated the effects of infliximab and etanercept on cardiac function and overall survival. Results showed possible exacerbation of heart failure with etanercept and increased risk of death with infliximab in patients with New York Heart Association (NYHA) class III or IV heart failure and left ventricular ejection fractions less than 35%.

Case reports have also described patients with worsening or new-onset heart failure on TNF inhibitors, including patients younger than 50 years and without identifiable cardiovascular risk factors.

Data analyses^31,34,35 from large clinical registries have reported no significant increase in heart failure attributable to TNF inhibitors. However, we have concerns about the methodology of these analyses.

Currently, anti-TNF therapy is contraindicated in patients with NYHA class III or IV heart failure. Data are inconclusive for patients with class I or II heart failure. Baseline echocardiography and cardiology consultation can be considered, with close monitoring and avoidance of high doses of TNF inhibitors. If heart failure develops in a patient on anti-TNF therapy, the drug should be discontinued and the patient should be evaluated further.³⁶

DEMYELINATING DISEASE, INCLUDING MULTIPLE SCLEROSIS

Anti-TNF agents have been associated with the onset or exacerbation of clinical symptoms and radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis.^37–40 Mohan et al³⁸ identified 19 cases of demyelinating events occurring after administration of anti-TNF agents in early 2001. In most cases, symptoms improved or resolved after therapy was stopped.

Optic neuritis,^41,42 bilateral optic neuropathy,⁴³ and aseptic meningitis⁴⁴ have also been reported, but these have occurred only rarely.

How common are these effects? Postmarketing surveillance in patients with rheumatoid arthritis yields an estimated incidence of demyelinating disorders of 1 per 1,000 patient-years with adalimumab therapy.⁴⁵ Complicating the assessment is an observed slight increase in risk of demyelinating conditions associated with inflammatory bowel disease.

Symptoms that should heighten the physician’s suspicion of this adverse effect include confusion, paresthesias, and ataxia. Patients on anti-TNF therapy who develop new visual symptoms should be checked for painless visual loss as a sign of early demyelinating disease.

Although data that conclusively link anti-TNF agents to multiple sclerosis are lacking, these drugs should not be initiated in patients who have a history of demyelinating disease, and treatment should be stopped promptly if the diagnosis is suspected.

MALIGNANCY

Whether anti-TNF therapy is directly linked to development of malignancies is difficult to determine. There are many confounding factors, including the risk of malignancy in underlying inflammatory disease and the concomitant use of other medications such as thiopurines, which have a known association with lymphoma.⁴⁶

The incidence of lymphoma is twice as high in rheumatoid arthritis patients as in the general population.⁴⁷ The risk is higher in those with more aggressive joint disease—the subset of rheumatoid arthritis patients who are more likely to be given anti-TNF agents.⁵

In patients with inflammatory bowel disease, the risk of cholangiocarcinoma is four times higher, and the risk of small-bowel adenocarcinoma is 16 to 18 times higher, but no increased risk of lymphoma has been identified in this population.^48,49

Data from six clinical trials of infliximab, including a long-term study of its safety in Crohn disease, suggest it poses no increase in overall risk of malignancy.^50–52 Similar results have been reported in patients with other rheumatic diseases.⁸ Information on this topic is constantly evolving, and studies range from case series to clinical trials to large patient registries.

The decision to use a TNF inhibitor should be based on the patient’s clinical picture and risk factors. Discussion of the risks and benefits of therapy with the patient should be clearly documented.

Non-Hodgkin lymphoma

Evidence about the risk of lymphoma with anti-TNF use is mixed, as up to two-thirds of patients on anti-TNF therapy have received concomitant nonbiologic immunosuppressive medications, making it difficult to determine the true risk from the biologic agents alone.⁵³ Current evidence both supports^9,53–56 and refutes^7,55,57–60 the idea that anti-TNF agents increase lymphoma risk.

In patients with inflammatory bowel disease, several population-based studies have not shown a clear increase in lymphoma risk with anti-TNF use.^56,59,60 Pedersen et al,⁶¹ in a meta-analysis of eight studies, confirmed these findings by showing no overall lymphoma risk in patients with inflammatory bowel disease.

However, a Canadian population-based study found a statistically significant increase in non-Hodgkin lymphoma in males with Crohn disease, with an incidence ratio of 3.63 (95% confidence interval [CI] 1.53–8.62).⁶¹ Additionally, Siegel et al⁶² found a significantly higher risk (6.1 cases per 10,000 patients) in patients treated with anti-TNF agents and thiopurines than in the general population (1.9 cases per 10,000 people). Although the difference was statistically significant, the overall risk is still very low.

Patients with rheumatoid arthritis seem to have a risk of lymphoma two to three times higher than in the general population. However, large population-based studies have not shown a statistically significant increase in the risk of lymphoma with anti-TNF therapy.⁶³

Hepatosplenic T-cell lymphoma is a rare subtype of peripheral T-cell non-Hodgkin lymphoma; 25 cases have been reported in patients receiving anti-TNF therapy.⁶⁴ Although the risk is extremely low (< 0.05%), physicians must carefully consider the risks and benefits of combination therapy, especially in young male patients with inflammatory bowel disease, since death is the usual outcome of this disease.^65–67

Skin cancers

Wolfe and Michaud⁸ evaluated malignancy risk in rheumatoid arthritis patients being treated with biologic agents, including TNF inhibitors, using a large longitudinal database. These data were compared with those of the US Surveillance, Epidemiology, and End-Results (SEER) national database. No increase in the overall cancer rate was seen in rheumatoid arthritis patients (standardized incidence ratio [SIR] 1.0, 95% CI 1.0–1.1).

However, melanoma was more common in rheumatoid arthritis patients compared with SEER rates (SIR 1.7, 95% CI 1.3–2.3).⁸ In addition, biologic therapy was associated with a higher (but not statistically significant) risk of melanoma (odds ratio [OR] 2.3, 95% CI 0.9–5.4) and a higher risk of nonmelanoma skin cancer (OR 1.5, 95% CI 1.2–1.8), but not of other types of cancer.⁸

INFECTION

Patients on anti-TNF therapy are at a higher risk of infection, ranging from minor to life-threatening bacterial infections, and including the reactivation of granulomatous and fungal infections. More importantly, these agents are similar to steroids in blunting signs of infection, which may delay diagnosis and treatment.

The management of infection in patients on anti-TNF medications varies from case to case. In general, patients with a minor infection that does not require hospitalization or intravenous antibiotics can continue the biologic therapy while taking oral antibiotics. TNF inhibitors must be held in the event of a major infection.

Consultation with an infectious disease specialist is recommended, especially in complex cases.

Bacterial infections

An increased risk of minor bacterial infections such as urinary tract and respiratory infections has been well documented in several randomized control trials of anti-TNF agents, though other studies have shown no such increase in risk.^33,51–59

The threshold for using antibiotics for a suspected bacterial infection is somewhat shifted in favor of treatment in patients on anti-TNF therapy. The reason is twofold: as previously noted, infections may be worse than they appear, because anti-TNF drugs can mask the signs and symptoms of a serious infection, and in patients on these drugs, an untreated bacterial infection may rapidly become life-threatening.

In general, broad-spectrum antibiotics are not warranted unless the source of infection is unclear or the patient is in danger of hemodynamic compromise.

Opportunistic infections

The association of anti-TNF agents with opportunistic infections could be viewed as an extension of their normal and intended therapeutic activity as potent immunosuppressive agents.⁶⁸ Rheumatoid arthritis and inflammatory bowel disease are usually associated with conditions and situations that predispose patients to opportunistic infections, such as decreased immune response, malnutrition or malabsorption, surgeries, and concomitant immunosuppressive medications.⁷ Combination therapy with other immunosuppressive drugs and older age appear to markedly increase the risk of opportunistic infections, including mycobacterial and fungal infections, in patients with inflammatory bowel disease.⁷

Overall, opportunistic infections represent a measurable risk of anti-TNF therapy, and awareness and vigilance are important, especially in areas where opportunistic infections such as histoplasmosis and coccidiomycosis are endemic.⁵⁰ Furthermore, physicians must be aware of the higher risk of opportunistic infections when multiple immunosuppressive drugs are used concurrently.

Anti-TNF agents increase the risk of de novo granulomatous infections and of reactivating such infections. Granuloma formation and intracellular destruction of mycobacteria depend on TNF. TNF is important in maintaining the anatomic integrity of granulomas where these organisms have been sequestered, and blocking TNF leads to breakdown of granulomas and release of virulent organisms.^69,70

TNF inhibitors increase the risk of reactivation of latent tuberculosis infection. The risk is greater with infliximab and adalimumab than with etanercept,^71,72 and it has been described with certolizumab.⁷⁴ Study results are varied thus far but show a risk of tuberculosis reactivation five to 30 times higher than in the general population, with tremendous variability in risk depending on background rates of previous exposure.

The absence of typical tuberculosis symptoms further complicates care in these cases. Fever, weight loss, and night sweats tend to be TNF-mediated and are therefore masked by anti-TNF agents, leading to atypical presentations. In addition, active tuberculosis infection associated with TNF inhibitors is more likely to involve extrapulmonary sites such as the skin and musculoskeletal system and to be disseminated at presentation.

A paradoxical worsening of tuberculosis symptoms may also be seen in patients with latent tuberculosis reactivation, especially after discontinuing anti-TNF therapy. This is thought to result from an immune reconstitution inflammatory syndrome.

The pretreatment evaluation should include a history of risk factors, a physical examination, and either a tuberculin skin test or an interferon-gamma-release assay. Interferon-gamma-release assays are particularly helpful in patients who have received bacille Calmette-Guérin vaccination. In patients who test positive or have been exposed, tuberculosis treatment should begin 4 weeks before starting anti-TNF therapy, though the optimal timing of antituberculosis agents is still controversial.^74–77

If tuberculosis develops in a patient on anti-TNF therapy, he or she should receive antituberculosis drugs. Anti-TNF therapy should be stopped and should be resumed after 2 months only if no other treatment option is available.⁷⁵

Invasive opportunistic fungal infections

Invasive opportunistic fungal infections have been reported with anti-TNF therapy, including histoplasmosis and coccidioidomycosis.^78–80 Most patients who had histoplasmosis were treated with other immunosuppressive therapies and resided in or were raised near the Ohio or Mississippi River valleys, where this disease is endemic. Similarly, most cases of coccidioidomycosis were in endemic areas of Arizona, California, and Nevada, and patients on concomitant immunosuppressive therapy.⁷⁸

Currently, there is no evidence to recommend obtaining Histoplasma capsulatum or Coccidioides immitis serologies before initiating anti-TNF therapy in patients in endemic areas.⁸¹ However, patients must be instructed to seek medical attention quickly for pulmonary or febrile illnesses.

Viral hepatitis infections

The data on hepatitis B and hepatitis C in patients on biologic therapies are mostly limited to case reports.

Hepatitis B. A small prospective study from Spain followed the liver biochemistry tests and hepatitis B status of 80 patients with Crohn disease treated with infliximab. Of three patients who were chronic hepatitis B carriers before starting infliximab, two experienced reactivation of hepatitis B after discontinuing infliximab, and one ultimately died. The third patient was treated with lamivudine concurrently with infliximab without clinical or biochemical changes during or after therapy.⁸²

Similar findings were observed in two patients with rheumatoid arthritis on treatment with infliximab. One of the patients required liver transplantation, and both were treated with lamivudine, resulting in normalization of liver function test results.^83,84

Recent reviews indicate that despite these findings, hepatitis B reactivation after anti-TNF withdrawal may not be common.⁸⁵ There are limited data on hepatitis B reactivation and associated liver dysfunction in patients with inflammatory bowel disease treated with immunosuppressants. In a retrospective multicenter trial by Loras et al⁸⁶ in patients with inflammatory bowel disease who had viral hepatitis, 36% of patients positive for hepatitis B surface antigen developed liver dysfunction, and six patients developed liver failure. In that study, treatment with more than two immunosuppressants was an independent predictor of hepatitis B reactivation.

Prolonged immunosuppression (longer than 3 months) has also been identified as an independent predictor of liver dysfunction (OR 3.06; 95% 95% CI 1.02–9.16).⁸⁷

The European Association for the Study of the Liver and the American Association for the Study of Liver Diseases recommend starting lamivudine before chemotherapy or immunomodulator or immunosuppressive therapy in hepatitis B virus carriers and continuing preventive treatment for at least 6 months after stopping immunomodulating drugs. Lamivudine at a dose of 100 mg/day may reduce the risk of reactivation of hepatitis B.^88–90 Tenofovir and entecavir may be useful alternatives in patients with hepatitis B who have never received nucleoside analogues. Hepatitis B reactivation did not occur in any of the 16 patients who received preventive entecavir treatment while receiving immunosuppressive treatments.^89,91

In patients receiving immunosuppressive therapy, hepatitis B reactivation is associated with significant morbidity and mortality. Although risk factors for reactivation of hepatitis B virus infection have been identified, we recommend preventive treatment for all carriers positive for hepatitis B surface antigen. This should be done regardless of the number, type, and dosage of immunosuppressants and regardless of hepatitis B virus DNA levels.⁹⁰

The frequency of hepatitis B and hepatitis C infection in patients with Crohn disease has been reported to be as high as 24%. The high incidence is thought to be secondary to multiple blood transfusions and surgeries.⁹² The use of biologic agents, including anti-TNF agents, in chronic hepatitis B virus- or hepatitis C virus-infected patients can lead to enhanced viral replication and hepatitis exacerbation.

Although active viral replication can occur during treatment with biologic agents, reactivation or exacerbation can also occur after the anti-TNF agent is stopped.⁸² This finding has prompted the recommendation that all candidates for biologic therapy be tested for hepatitis B immunization status, followed by immunization in nonimmune patients before starting anti-TNF therapy.^93,94

Hepatitis C. There are no guidelines that adequately address the use of anti-TNF agents in patients with chronic hepatitis C infection.

Several small retrospective studies in rheumatoid arthritis patients with hepatitis C have shown that TNF inhibitors can be safely used without worsening liver function tests or changing the viral load.^95–98 This is reassuring and provides the subspecialist with another treatment option, as other therapies such as disease-modifying antirheumatic drugs and steroids are known to aggravate viral hepatitis and increase the risk of viremia.⁹⁶

Although small retrospective studies and one large randomized double-blind placebo-controlled trial have shown TNF inhibitors to be relatively safe in rheumatoid arthritis patients with hepatitis C, their use in these patients should be considered only with caution if they have evidence of hepatic synthetic dysfunction (eg, hypoalbuminemia, thrombocytopenia, increased international normalized ratio). The American College of Rheumatology recommends avoiding TNF inhibitors in Child-Pugh classes B and C.⁹⁹

PREGNANCY

Physicians caring for patients with rheumatoid arthritis and inflammatory bowel disease must be aware of how these diseases affect fecundity and fertility and how the medications can affect conception and pregnancy. Many patients have difficulty conceiving while their autoimmune disease is active, and better disease control may improve fecundity and result in unanticipated pregnancy. Patients should be advised of the need for contraception if pregnancy is ill-advised or undesired.

Many patients seek advice about teratogenicity before conceiving, or seek guidance about rheumatoid arthritis and inflammatory bowel disease treatment while pregnant.

Several studies have reported a higher risk of adverse pregnancy outcomes in patients with rheumatoid arthritis and inflammatory bowel disease than in the general population.^99–105 In inflammatory bowel disease, the odds of a premature delivery or having a low-birth-weight child are twice as high as in the normal population.^100,103 Higher rates of cesarean delivery and stillbirth have also been reported. The main predisposing factor appears to be the disease activity at the time of conception, as active disease seems to be linked to adverse pregnancy outcomes.

Treatment with anti-TNF agents may rapidly achieve and maintain remission, raising the question of the safety of continued anti-TNF use during pregnancy. The FDA classifies anti-TNF agents as category B drugs, as animal studies have not demonstrated fetal risk, and no well-controlled prospective study has yet been conducted with pregnant women.

In an observational study, Schnitzler et al¹⁰⁵ assessed the outcomes of 42 pregnancies in 35 patients with inflammatory bowel disease receiving either infliximab or adalimumab during pregnancy, compared with 56 pregnancies in 45 healthy patients without inflammatory bowel disease. There was no statistical difference in abortion rates between patients receiving anti-TNF agents and healthy women without inflammatory bowel disease (21% vs 14%, P = .4234). There was also no significant difference observed in birth weight, birth length, or cranial circumference of the children between the two groups. However, pregnancies with direct exposure to anti-TNF agents resulted in a higher frequency of premature delivery (25% vs 6%, P = .023).

Similar results were noted from the Crohn’s Therapy, Resource, Evaluation, and Assessment Tool, or TREAT, registry, as well as from a large systematic review by Vinet et al¹⁰⁶ and case reports of rheumatoid arthritis and inflammatory bowel disease in women exposed to anti-TNF agents during pregnancy.

In addition, results from a recent systematic review of 38 studies of anti-TNF use and fetal risk, with a total of 437 women (189 on infliximab, 230 on adalimumab, 18 on certolizumab pegol), showed similar results.¹⁰⁷ In pregnancies exposed to anti-TNF agents, the rates of congenital abnormalities (3.4%), fetal deaths (8.5%), and preterm births (2.7%) were similar to those in the general population.

For patients in disease remission on TNF inhibitors, it is reasonable to continue these agents during pregnancy after careful discussion with the patient. Fetal safety and infant immunization response after delivery are the primary concerns in these cases.

Both infliximab and adalimumab cross the placenta and remain detectable in the baby’s circulation 4 months (for adalimumab) to 6 months (for infliximab) after delivery. It is currently recommended that infliximab be stopped at 32 weeks of gestation for the remainder of the pregnancy and that adalimumab be stopped at 34 to 36 weeks, given a planned 40-week gestation.

Certolizumab does not cross the placenta in significant amounts and should be continued throughout pregnancy; drug levels in infants were shown to be less than 2 μg/mL, even when dosed the week of delivery.^108–112

TAKE-HOME POINTS

• All health care providers of patients with rheumatoid arthritis and inflammatory bowel disease should be familiar with anti-TNF agents used in treating these diseases.
• The benefits of controlling the disease far outweigh the risks of therapy when used appropriately.
• Care of these patients should be multidisciplinary, with clear communication between primary care physician and specialist.
• Patient education and monitoring combined with prompt communication between primary care physician and specialist are key.

Answer

The radiograph shows a masslike density within the left suprahilar and mediastinal region, most likely consistent with a carcinoma. Given the entire clinical picture, this patient likely has a primary lung carcinoma that metastasized to the brain.  

Answer

The radiograph shows a masslike density within the left suprahilar and mediastinal region, most likely consistent with a carcinoma. Given the entire clinical picture, this patient likely has a primary lung carcinoma that metastasized to the brain.  

Answer

The radiograph shows a masslike density within the left suprahilar and mediastinal region, most likely consistent with a carcinoma. Given the entire clinical picture, this patient likely has a primary lung carcinoma that metastasized to the brain.  

A 78-year-old woman presented to the emergency department (ED) complaining of shortness of breath, a dry nonproductive cough, fatigue, hypoxia, and general malaise lasting for several months and worsening over a two-week period. She denied having fever, chills, hemoptysis, weight loss, headache, rashes, or joint pain. She reported sweats, decrease in appetite, wheezing, cough without sputum production, and slight swelling of the legs. The patient complained of chest pain upon admission, but it resolved quickly.

The patient, a retired widow with five grown children, denied recent surgery or exposure to sick people, had not travelled, and reported no changes in her home environment. She claimed to have no pets but admitted to currently smoking about four cigarettes a day; she had previously smoked, on average, three packs of cigarettes per day for 60 years. She denied using alcohol or drugs, including intravenous agents.

The patient’s medical history was significant for paroxysmal atrial fibrillation. She had also been diagnosed with chronic obstructive pulmonary disease (COPD), transient ischemic attack, patent foramen ovale, hyperlipidemia, seizure disorder, and hypothyroidism. She had no known HIV risk factors and had had no exposure to asbestos or tuberculosis.

The patient’s current medications included amiodarone (200 mg/d) for four years; valproic acid (500 mg/d); aspirin (325 mg/d); levothyroxine (50 g/d); rosuvastatin (10 mg/d); daily warfarin, dosed according to the international normalized ratio (INR); and budesonide/formoterol (160/4.5 mg, one puff bid). She denied having any drug allergies.

Physical examination in the ED revealed a pulse of 63 beats/min; blood pressure, 108/50 mm Hg; and respiratory rate, 16 to 20 breaths/min. The patient’s O₂ saturation was 84% on room air; 82% to 84% on 4 L to 6 L of supplemental oxygen; 87% to 92% with a venturi mask; and 95% on biphasic positive airway pressure (BiPAP) device. She was afebrile with hypoxia and able to speak in full sentences. Crackles were detected in the upper lung fields, best heard anteriorly, as well as a few scattered wheezes and rhonchi. Her heart sounds were normal with a regular rhythm; her extremities exhibited trace edema bilaterally. The remainder of the physical exam was normal.

The patient’s laboratory values included a normal white blood cell (WBC) count, elevated lactic acid dehydrogenase (LDH) at 448 IU/L (reference range, 84 to 246 IU/L), and no eosinophils. The erythrocyte sedimentation rate (ESR) was not measured on admission. Blood analysis of her N-terminal pro-brain natriuretic peptide (NT-proBNP) was 4,877 pg/mL; for women older than 75, a level higher than 1,800 pg/mL is abnormal.

A chest x-ray was performed on admission, showing hyperinflation of the lungs with mild coarsening of the lung markings. A bandlike area of opacity in the right lower lobe with bilateral apical pleural thickening was noted (see Figure 1). Noncontrast CT of the chest revealed diffuse upper lobe ground glass opacities in both lungs, extending into the right middle lobe and lingula as well the superior segments of the lower lobes, with areas of emphysema and septal thickening. Numerous nodules, some of which appeared cavitary, were apparent in the lower lobes.

A two-dimensional echocardiogram demonstrated normal left ventricular size and systolic function, mild tricuspid regurgitation without evidence of ­pulmonary hypertension, and mild left atrial enlargement.

The patient was admitted to the cardiac unit for evaluation. While there, she received one dose of methylprednisolone (125 mg IV), three doses of ipratropium bromide/albuterol, one dose of ceftriaxone (1 g IV), and one dose of azithromycin (500 mg po). In the absence of significant leg edema and an elevation of jugular venous distention with a normal two-dimensional echocardiogram, heart failure was ruled out. The chest pains reported on initial presentation were ultimately felt to be noncardiac in nature.

After the patient was transferred to the medical floor with an initial diagnosis of exacerbation of her COPD, she was treated with antibiotics, nebulizers, and corticosteroids. She continued to experience episodes of O₂ desaturation while on 4 L to 6 L of oxygen via nasal cannula and on a venturi mask. She was then placed on a BiPAP device, set to 12/5, and 50% Fio₂ (fraction of inspired oxygen), which improved her oxygenation.

Her hypoxia prompted further radiographic studies. The resulting chest CT scan showed ground glass opacities located primarily in the upper lung areas, greater on the right than on the left side (see Figure 2). The radiologist suggested that the hypoxia was caused by an infection, but because the patient’s presenting symptoms were chronic in nature, drug-induced causes were considered as well. Amiodarone was discontinued.

Cardiology was consulted and agreed that stopping amiodarone was acceptable since the patient was in sinus rhythm at the time. The patient continued to take antibiotics and prednisone. Her symptoms slowly improved during hospitalization, and she required less oxygen. Based on the patient’s presentation, physical exam findings, imaging studies, and laboratory findings, amiodarone-induced pulmonary toxicity (APT) was diagnosed.

She was discharged home on supplemental oxygen at 4 L via cannula, a tapering dosage of prednisone, and metered-dose inhalers for fluticasone/salmeterol and tiotropium bromide. She also had outpatient appointments scheduled, one with the pulmonologist to follow up on her imaging studies and to manage the prednisone taper and the other with the cardiologist to manage her atrial fibrillation.

At pulmonology two months later, she had a chest x-ray (see Figure 3) and pulmonary function tests (PFTs). The patient reported feeling progressively better in the past month. Her dyspnea on exertion had improved, and she did not require supplemental oxygen anymore. She stopped smoking cigarettes.

The patient continued to use fluticasone/salmeterol but stopped tiotropium bromide. On physical exam, her O₂ saturation was 95% on room air, heart rhythm and rate were regular, and her lungs revealed very minimal crackles at the right base but were otherwise clear.

The plan specified continuing the prednisone taper. The patient was asked to call the office if she had any worsening shortness of breath, cough, and sputum production. She was also encouraged to continue refraining from smoking cigarettes. This patient had done very well, with near complete resolution of symptoms and a clear chest x-ray.

Continue reading for discussion... 

DISCUSSION

Amiodarone, a highly effective antiarrhythmic drug, is FDA approved for suppressing ventricular fibrillation and ventricular tachycardia. It is also used off-label as a second- or third-line choice for atrial fibrillation.¹

Standard of care requires that, prior to starting amiodarone therapy, patients have a baseline chest x-ray and PFTs with diffusing capacity performed. Thereafter, the patient should be monitored with annual chest x-rays, with one performed promptly if new symptoms develop. Serial PFTs have not offered any benefit for monitoring, but a decrease of more than 15% in total lung capacity or more than 20% in diffusing capacity from baseline is consistent with APT.²

Adverse effects, both cardiac and noncardiac, are common with amiodarone therapy. They include proarrhythmias, bradycardia, and heart block, as well as thyroid and liver dysfunctions; dermatologic conditions such as blue-gray discoloration of the skin and photosensitivity; neurologic effects such as ataxia, paresthesias, and tremor; ocular problems, including corneal microdeposits; gastrointestinal problems such as nausea, anorexia, and consti­pation; and lung problems such as pulmonary toxicity, pleural effusion, and pleural thickening.^3-6 Of these, pulmonary toxicity is the most severe and life threatening.⁷

APT, also known as amiodarone pneumonitis and amiodarone lung, typically manifests from a few months to a year and a half after treatment is commenced.⁶ APT can occur even after the drug is discontinued, because amiodarone has a very long elimination half-life of approximately 15 to 45 days and a tendency to concentrate in organs with high blood perfusion and in adipose tissues.⁸ Patients taking 400 mg/d for two months or longer or 200 mg/d for more than two years are considered at higher risk for APT.⁹ The severity of disease appears to correlate with the cumulative dose and length of treatment.¹⁰

Numerous risk factors for pulmonary toxicity have been reported, including high drug dosage, pre-existing lung disease, patient age, and prior surgery (see Table 1).¹¹ According to an analysis of a database of 237 patients, only age and duration of amiodarone therapy were significant risk factors for APT.⁹ Its incidence is not precisely known; reported rates range from 1% to 17%.^6,12,13

Presentation with such nonspecific symptoms as shortness of breath, nonproductive cough, fatigue, hypoxia, and general malaise is typical for many pulmonary and cardiac illnesses (see Table 2), making APT difficult to diagnose.¹⁴ Occasionally, rapid onset with progression to pneumonitis and respiratory failure masquerades as acute respiratory distress syndrome (ARDS).¹⁵

Notable, however, is that APT can manifest with nonproductive cough and dyspnea in 50% to 75% of cases. In addition, presenting symptoms will include fever (33% to 50% of cases) with associated malaise, fatigue, chest pain, and weight loss. In patients with APT, the physical exam usually reveals bilateral crackles on inspiration, but diffuse rales may be heard as well.¹¹

Laboratory studies are not very helpful in diagnosing APT. Patients may present with nonspecific elevated WBCs without eosinophilia and an elevated LDH level.¹¹ An elevated ESR may be detected before symptoms of APT manifest and can be present at the time of diagnosis.⁶

Imaging studies are far more helpful and specific in diagnosing APT. The typical chest x-ray shows bilateral patchy diffuse infiltrates.¹² CT of the chest is usually more revealing, demonstrating ground glass opacities in the periphery and subpleural thickening, especially where infiltrates are denser. This thickening may result in pleuritic chest pain.⁶

The right upper lobe is more often affected in these cases than the left lung.⁶ Numerous pulmonary nodules in the upper lobes are found rarely and can be confused with lung cancer. These nodules are likely the result of an accumulation of the drug in areas of previous inflammation; a lung mass should prompt the addition of APT in the differential.^2,16

APT is a diagnosis of exclusion, requiring clinical suspicion, drug history, imaging, and consideration of the differential. The presence of three or more clinical factors supports a diagnosis of APT (see Table 3).¹¹

Once APT is recognized, the first action is to have the patient stop taking amiodarone, followed by the administration of corticosteroids (eg, prednisone 40 to 60 mg/d¹¹) for four to 12 months.¹⁷ Patients, especially those with underlying lung disease, will typically require temporary oxygen supplementation until hypoxia resolves. Even after the drug has been discontinued, some patients experience worsening symptoms before they see improvement simply because the drug can persist in lung tissue for up to a year following cessation of therapy.⁶

If APT is diagnosed early, the prognosis is favorable. In one study, a significant number of APT patients stabilized or improved after withdrawal of the drug, regardless of concurrent treatment with corticosteroids.¹⁸ Follow-up studies, both imaging and PFT, indicate complete clearing of lung opacities in the majority of patients treated for APT.¹⁹ Radiologic improvement may be seen six months after cessation of amiodarone.²⁰ Patients who develop ARDS tend to do poorly and have a mortality rate of approximately 50%.¹¹

Continue reading for the conclusion...

CONCLUSION

Among patients who are taking long-term or high-dose amiodarone, particularly those older than 60, new-onset nonproductive cough and dyspnea signal the need for pulmonary and cardiac work-up. Once the diagnosis of APT is made, treatment is straightforward: Withdraw the amiodarone, and initiate corticosteroid therapy.

REFERENCES

1. Fuster V, Rydén LE, Asinger RW, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation); North American Society of Pacing and Electrophysiology. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. Circulation. 2001; 104(17):2118-2150.

2. Jarand J, Lee A, Leigh R. Amiodaronoma: an unusual form of amiodarone-induced pulmonary toxicity. CMAJ. 2007;176(10):1411-1413.

3. Connolly S. Evidence-based analysis of amiodarone efficacy and safety. Circulation. 1999;100:2025-2034.

4. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet. 1997;350(9089):1417-1424.

5. Pollak PT. Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifestations. Am J Cardiol. 1999;84(9A):37R-45R.

6. Camus P, Martin W, Rosenow E. Amiodarone pulmonary toxicity. Clin Chest Med. 2004;25(1):65-75.

7. Rady MY, Ryan T, Starr NJ. Preoperative therapy with amiodarone and the incidence of acute organ dysfunction after cardiac surgery. Anesth Analg. 1997;85(3):489-497.

8. Canada A, Lesko L, Haffajee C, et al. Amiodarone for tachyarrhythmias: kinetics, and efficacy. Drug Intell Clin Pharm. 1983;17(2):100-104.

9. Ernawati DK, Stafford L, Hughes JD. Amiodarone-induced pulmonary toxicity. Br J Clin Pharmacol. 2008;66(1):82-87.

10. Liu FL, Cohen RD, Downar E, et al. Amiodarone pulmonary toxicity: functional and ultrastructural evaluation. Thorax. 1986;41(2):100-105.

11. Chan E, King TE. Amiodarone pulmonary toxicity. UpToDate. 2013. www.uptodate.com/contents/amiodarone-pulmonary-toxicity. Accessed January 17, 2014.

12. Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J. 2009;16(2):43-48.

13. Jackevicius CA, Tom A, Essebag V, et al. Population-level incidence and risk factors for pulmonary toxicity associated with amiodarone. Am J Cardiol. 2011;108:705-710.

14. Jessurun G, Crijns H. Amiodarone pulmonary toxicity [editorial]. BMJ. 1997;314(7081):619-620.

15. Nacca N, Castigliano B, Yuhico L, et al. Severe amiodarone induced pulmonary toxicity. J Thorac Dis. 2012;4(6):667-670.

16. Arnon R, Raz I, Chajek-Shaul T, et al. Amiodarone pulmonary toxicity presenting as a solitary lung mass. Chest. 1988;93(2):425-427.

17. Yamada Y, Shiga T, Matsuda N, et al. Incidence and predictors of pulmonary toxicity in Japanese patients receiving low-dose amiodarone. Circ J. 2007;71(10):1610-1616.

18. Coudert B, Bailly F, Lombard JN, et al. Amiodarone pneumonitis: bronchoalveolar lavage findings in 15 patients and review of the literature. Chest. 1992;102(4):1005-1012.

19. Vernhet H, Bousquet C, Durand G, et al. Reversible amiodarone-induced lung disease: HRCT findings. Eur Radiol. 2001;11(9):1697-1703.

20. Olson LK, Forrest JV, Friedman PJ, et al. Pneumonitis after amiodarone therapy. Radiology. 1984;150(2):327-330.

A 78-year-old woman presented to the emergency department (ED) complaining of shortness of breath, a dry nonproductive cough, fatigue, hypoxia, and general malaise lasting for several months and worsening over a two-week period. She denied having fever, chills, hemoptysis, weight loss, headache, rashes, or joint pain. She reported sweats, decrease in appetite, wheezing, cough without sputum production, and slight swelling of the legs. The patient complained of chest pain upon admission, but it resolved quickly.

The patient, a retired widow with five grown children, denied recent surgery or exposure to sick people, had not travelled, and reported no changes in her home environment. She claimed to have no pets but admitted to currently smoking about four cigarettes a day; she had previously smoked, on average, three packs of cigarettes per day for 60 years. She denied using alcohol or drugs, including intravenous agents.

The patient’s medical history was significant for paroxysmal atrial fibrillation. She had also been diagnosed with chronic obstructive pulmonary disease (COPD), transient ischemic attack, patent foramen ovale, hyperlipidemia, seizure disorder, and hypothyroidism. She had no known HIV risk factors and had had no exposure to asbestos or tuberculosis.

The patient’s current medications included amiodarone (200 mg/d) for four years; valproic acid (500 mg/d); aspirin (325 mg/d); levothyroxine (50 g/d); rosuvastatin (10 mg/d); daily warfarin, dosed according to the international normalized ratio (INR); and budesonide/formoterol (160/4.5 mg, one puff bid). She denied having any drug allergies.

Physical examination in the ED revealed a pulse of 63 beats/min; blood pressure, 108/50 mm Hg; and respiratory rate, 16 to 20 breaths/min. The patient’s O₂ saturation was 84% on room air; 82% to 84% on 4 L to 6 L of supplemental oxygen; 87% to 92% with a venturi mask; and 95% on biphasic positive airway pressure (BiPAP) device. She was afebrile with hypoxia and able to speak in full sentences. Crackles were detected in the upper lung fields, best heard anteriorly, as well as a few scattered wheezes and rhonchi. Her heart sounds were normal with a regular rhythm; her extremities exhibited trace edema bilaterally. The remainder of the physical exam was normal.

The patient’s laboratory values included a normal white blood cell (WBC) count, elevated lactic acid dehydrogenase (LDH) at 448 IU/L (reference range, 84 to 246 IU/L), and no eosinophils. The erythrocyte sedimentation rate (ESR) was not measured on admission. Blood analysis of her N-terminal pro-brain natriuretic peptide (NT-proBNP) was 4,877 pg/mL; for women older than 75, a level higher than 1,800 pg/mL is abnormal.

A chest x-ray was performed on admission, showing hyperinflation of the lungs with mild coarsening of the lung markings. A bandlike area of opacity in the right lower lobe with bilateral apical pleural thickening was noted (see Figure 1). Noncontrast CT of the chest revealed diffuse upper lobe ground glass opacities in both lungs, extending into the right middle lobe and lingula as well the superior segments of the lower lobes, with areas of emphysema and septal thickening. Numerous nodules, some of which appeared cavitary, were apparent in the lower lobes.

A two-dimensional echocardiogram demonstrated normal left ventricular size and systolic function, mild tricuspid regurgitation without evidence of ­pulmonary hypertension, and mild left atrial enlargement.

The patient was admitted to the cardiac unit for evaluation. While there, she received one dose of methylprednisolone (125 mg IV), three doses of ipratropium bromide/albuterol, one dose of ceftriaxone (1 g IV), and one dose of azithromycin (500 mg po). In the absence of significant leg edema and an elevation of jugular venous distention with a normal two-dimensional echocardiogram, heart failure was ruled out. The chest pains reported on initial presentation were ultimately felt to be noncardiac in nature.

After the patient was transferred to the medical floor with an initial diagnosis of exacerbation of her COPD, she was treated with antibiotics, nebulizers, and corticosteroids. She continued to experience episodes of O₂ desaturation while on 4 L to 6 L of oxygen via nasal cannula and on a venturi mask. She was then placed on a BiPAP device, set to 12/5, and 50% Fio₂ (fraction of inspired oxygen), which improved her oxygenation.

Her hypoxia prompted further radiographic studies. The resulting chest CT scan showed ground glass opacities located primarily in the upper lung areas, greater on the right than on the left side (see Figure 2). The radiologist suggested that the hypoxia was caused by an infection, but because the patient’s presenting symptoms were chronic in nature, drug-induced causes were considered as well. Amiodarone was discontinued.

Cardiology was consulted and agreed that stopping amiodarone was acceptable since the patient was in sinus rhythm at the time. The patient continued to take antibiotics and prednisone. Her symptoms slowly improved during hospitalization, and she required less oxygen. Based on the patient’s presentation, physical exam findings, imaging studies, and laboratory findings, amiodarone-induced pulmonary toxicity (APT) was diagnosed.

She was discharged home on supplemental oxygen at 4 L via cannula, a tapering dosage of prednisone, and metered-dose inhalers for fluticasone/salmeterol and tiotropium bromide. She also had outpatient appointments scheduled, one with the pulmonologist to follow up on her imaging studies and to manage the prednisone taper and the other with the cardiologist to manage her atrial fibrillation.

At pulmonology two months later, she had a chest x-ray (see Figure 3) and pulmonary function tests (PFTs). The patient reported feeling progressively better in the past month. Her dyspnea on exertion had improved, and she did not require supplemental oxygen anymore. She stopped smoking cigarettes.

The patient continued to use fluticasone/salmeterol but stopped tiotropium bromide. On physical exam, her O₂ saturation was 95% on room air, heart rhythm and rate were regular, and her lungs revealed very minimal crackles at the right base but were otherwise clear.

The plan specified continuing the prednisone taper. The patient was asked to call the office if she had any worsening shortness of breath, cough, and sputum production. She was also encouraged to continue refraining from smoking cigarettes. This patient had done very well, with near complete resolution of symptoms and a clear chest x-ray.

Continue reading for discussion... 

DISCUSSION

Amiodarone, a highly effective antiarrhythmic drug, is FDA approved for suppressing ventricular fibrillation and ventricular tachycardia. It is also used off-label as a second- or third-line choice for atrial fibrillation.¹

Standard of care requires that, prior to starting amiodarone therapy, patients have a baseline chest x-ray and PFTs with diffusing capacity performed. Thereafter, the patient should be monitored with annual chest x-rays, with one performed promptly if new symptoms develop. Serial PFTs have not offered any benefit for monitoring, but a decrease of more than 15% in total lung capacity or more than 20% in diffusing capacity from baseline is consistent with APT.²

Adverse effects, both cardiac and noncardiac, are common with amiodarone therapy. They include proarrhythmias, bradycardia, and heart block, as well as thyroid and liver dysfunctions; dermatologic conditions such as blue-gray discoloration of the skin and photosensitivity; neurologic effects such as ataxia, paresthesias, and tremor; ocular problems, including corneal microdeposits; gastrointestinal problems such as nausea, anorexia, and consti­pation; and lung problems such as pulmonary toxicity, pleural effusion, and pleural thickening.^3-6 Of these, pulmonary toxicity is the most severe and life threatening.⁷

APT, also known as amiodarone pneumonitis and amiodarone lung, typically manifests from a few months to a year and a half after treatment is commenced.⁶ APT can occur even after the drug is discontinued, because amiodarone has a very long elimination half-life of approximately 15 to 45 days and a tendency to concentrate in organs with high blood perfusion and in adipose tissues.⁸ Patients taking 400 mg/d for two months or longer or 200 mg/d for more than two years are considered at higher risk for APT.⁹ The severity of disease appears to correlate with the cumulative dose and length of treatment.¹⁰

Numerous risk factors for pulmonary toxicity have been reported, including high drug dosage, pre-existing lung disease, patient age, and prior surgery (see Table 1).¹¹ According to an analysis of a database of 237 patients, only age and duration of amiodarone therapy were significant risk factors for APT.⁹ Its incidence is not precisely known; reported rates range from 1% to 17%.^6,12,13

Presentation with such nonspecific symptoms as shortness of breath, nonproductive cough, fatigue, hypoxia, and general malaise is typical for many pulmonary and cardiac illnesses (see Table 2), making APT difficult to diagnose.¹⁴ Occasionally, rapid onset with progression to pneumonitis and respiratory failure masquerades as acute respiratory distress syndrome (ARDS).¹⁵

Notable, however, is that APT can manifest with nonproductive cough and dyspnea in 50% to 75% of cases. In addition, presenting symptoms will include fever (33% to 50% of cases) with associated malaise, fatigue, chest pain, and weight loss. In patients with APT, the physical exam usually reveals bilateral crackles on inspiration, but diffuse rales may be heard as well.¹¹

Laboratory studies are not very helpful in diagnosing APT. Patients may present with nonspecific elevated WBCs without eosinophilia and an elevated LDH level.¹¹ An elevated ESR may be detected before symptoms of APT manifest and can be present at the time of diagnosis.⁶

Imaging studies are far more helpful and specific in diagnosing APT. The typical chest x-ray shows bilateral patchy diffuse infiltrates.¹² CT of the chest is usually more revealing, demonstrating ground glass opacities in the periphery and subpleural thickening, especially where infiltrates are denser. This thickening may result in pleuritic chest pain.⁶

The right upper lobe is more often affected in these cases than the left lung.⁶ Numerous pulmonary nodules in the upper lobes are found rarely and can be confused with lung cancer. These nodules are likely the result of an accumulation of the drug in areas of previous inflammation; a lung mass should prompt the addition of APT in the differential.^2,16

APT is a diagnosis of exclusion, requiring clinical suspicion, drug history, imaging, and consideration of the differential. The presence of three or more clinical factors supports a diagnosis of APT (see Table 3).¹¹

Once APT is recognized, the first action is to have the patient stop taking amiodarone, followed by the administration of corticosteroids (eg, prednisone 40 to 60 mg/d¹¹) for four to 12 months.¹⁷ Patients, especially those with underlying lung disease, will typically require temporary oxygen supplementation until hypoxia resolves. Even after the drug has been discontinued, some patients experience worsening symptoms before they see improvement simply because the drug can persist in lung tissue for up to a year following cessation of therapy.⁶

If APT is diagnosed early, the prognosis is favorable. In one study, a significant number of APT patients stabilized or improved after withdrawal of the drug, regardless of concurrent treatment with corticosteroids.¹⁸ Follow-up studies, both imaging and PFT, indicate complete clearing of lung opacities in the majority of patients treated for APT.¹⁹ Radiologic improvement may be seen six months after cessation of amiodarone.²⁰ Patients who develop ARDS tend to do poorly and have a mortality rate of approximately 50%.¹¹

Continue reading for the conclusion...

CONCLUSION

Among patients who are taking long-term or high-dose amiodarone, particularly those older than 60, new-onset nonproductive cough and dyspnea signal the need for pulmonary and cardiac work-up. Once the diagnosis of APT is made, treatment is straightforward: Withdraw the amiodarone, and initiate corticosteroid therapy.

REFERENCES

1. Fuster V, Rydén LE, Asinger RW, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation); North American Society of Pacing and Electrophysiology. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. Circulation. 2001; 104(17):2118-2150.

2. Jarand J, Lee A, Leigh R. Amiodaronoma: an unusual form of amiodarone-induced pulmonary toxicity. CMAJ. 2007;176(10):1411-1413.

3. Connolly S. Evidence-based analysis of amiodarone efficacy and safety. Circulation. 1999;100:2025-2034.

4. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet. 1997;350(9089):1417-1424.

5. Pollak PT. Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifestations. Am J Cardiol. 1999;84(9A):37R-45R.

6. Camus P, Martin W, Rosenow E. Amiodarone pulmonary toxicity. Clin Chest Med. 2004;25(1):65-75.

7. Rady MY, Ryan T, Starr NJ. Preoperative therapy with amiodarone and the incidence of acute organ dysfunction after cardiac surgery. Anesth Analg. 1997;85(3):489-497.

8. Canada A, Lesko L, Haffajee C, et al. Amiodarone for tachyarrhythmias: kinetics, and efficacy. Drug Intell Clin Pharm. 1983;17(2):100-104.

9. Ernawati DK, Stafford L, Hughes JD. Amiodarone-induced pulmonary toxicity. Br J Clin Pharmacol. 2008;66(1):82-87.

10. Liu FL, Cohen RD, Downar E, et al. Amiodarone pulmonary toxicity: functional and ultrastructural evaluation. Thorax. 1986;41(2):100-105.

11. Chan E, King TE. Amiodarone pulmonary toxicity. UpToDate. 2013. www.uptodate.com/contents/amiodarone-pulmonary-toxicity. Accessed January 17, 2014.

12. Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J. 2009;16(2):43-48.

13. Jackevicius CA, Tom A, Essebag V, et al. Population-level incidence and risk factors for pulmonary toxicity associated with amiodarone. Am J Cardiol. 2011;108:705-710.

14. Jessurun G, Crijns H. Amiodarone pulmonary toxicity [editorial]. BMJ. 1997;314(7081):619-620.

15. Nacca N, Castigliano B, Yuhico L, et al. Severe amiodarone induced pulmonary toxicity. J Thorac Dis. 2012;4(6):667-670.

16. Arnon R, Raz I, Chajek-Shaul T, et al. Amiodarone pulmonary toxicity presenting as a solitary lung mass. Chest. 1988;93(2):425-427.

17. Yamada Y, Shiga T, Matsuda N, et al. Incidence and predictors of pulmonary toxicity in Japanese patients receiving low-dose amiodarone. Circ J. 2007;71(10):1610-1616.

18. Coudert B, Bailly F, Lombard JN, et al. Amiodarone pneumonitis: bronchoalveolar lavage findings in 15 patients and review of the literature. Chest. 1992;102(4):1005-1012.

19. Vernhet H, Bousquet C, Durand G, et al. Reversible amiodarone-induced lung disease: HRCT findings. Eur Radiol. 2001;11(9):1697-1703.

20. Olson LK, Forrest JV, Friedman PJ, et al. Pneumonitis after amiodarone therapy. Radiology. 1984;150(2):327-330.

A 78-year-old woman presented to the emergency department (ED) complaining of shortness of breath, a dry nonproductive cough, fatigue, hypoxia, and general malaise lasting for several months and worsening over a two-week period. She denied having fever, chills, hemoptysis, weight loss, headache, rashes, or joint pain. She reported sweats, decrease in appetite, wheezing, cough without sputum production, and slight swelling of the legs. The patient complained of chest pain upon admission, but it resolved quickly.

The patient, a retired widow with five grown children, denied recent surgery or exposure to sick people, had not travelled, and reported no changes in her home environment. She claimed to have no pets but admitted to currently smoking about four cigarettes a day; she had previously smoked, on average, three packs of cigarettes per day for 60 years. She denied using alcohol or drugs, including intravenous agents.

The patient’s medical history was significant for paroxysmal atrial fibrillation. She had also been diagnosed with chronic obstructive pulmonary disease (COPD), transient ischemic attack, patent foramen ovale, hyperlipidemia, seizure disorder, and hypothyroidism. She had no known HIV risk factors and had had no exposure to asbestos or tuberculosis.

The patient’s current medications included amiodarone (200 mg/d) for four years; valproic acid (500 mg/d); aspirin (325 mg/d); levothyroxine (50 g/d); rosuvastatin (10 mg/d); daily warfarin, dosed according to the international normalized ratio (INR); and budesonide/formoterol (160/4.5 mg, one puff bid). She denied having any drug allergies.

Physical examination in the ED revealed a pulse of 63 beats/min; blood pressure, 108/50 mm Hg; and respiratory rate, 16 to 20 breaths/min. The patient’s O₂ saturation was 84% on room air; 82% to 84% on 4 L to 6 L of supplemental oxygen; 87% to 92% with a venturi mask; and 95% on biphasic positive airway pressure (BiPAP) device. She was afebrile with hypoxia and able to speak in full sentences. Crackles were detected in the upper lung fields, best heard anteriorly, as well as a few scattered wheezes and rhonchi. Her heart sounds were normal with a regular rhythm; her extremities exhibited trace edema bilaterally. The remainder of the physical exam was normal.

The patient’s laboratory values included a normal white blood cell (WBC) count, elevated lactic acid dehydrogenase (LDH) at 448 IU/L (reference range, 84 to 246 IU/L), and no eosinophils. The erythrocyte sedimentation rate (ESR) was not measured on admission. Blood analysis of her N-terminal pro-brain natriuretic peptide (NT-proBNP) was 4,877 pg/mL; for women older than 75, a level higher than 1,800 pg/mL is abnormal.

A chest x-ray was performed on admission, showing hyperinflation of the lungs with mild coarsening of the lung markings. A bandlike area of opacity in the right lower lobe with bilateral apical pleural thickening was noted (see Figure 1). Noncontrast CT of the chest revealed diffuse upper lobe ground glass opacities in both lungs, extending into the right middle lobe and lingula as well the superior segments of the lower lobes, with areas of emphysema and septal thickening. Numerous nodules, some of which appeared cavitary, were apparent in the lower lobes.

A two-dimensional echocardiogram demonstrated normal left ventricular size and systolic function, mild tricuspid regurgitation without evidence of ­pulmonary hypertension, and mild left atrial enlargement.

The patient was admitted to the cardiac unit for evaluation. While there, she received one dose of methylprednisolone (125 mg IV), three doses of ipratropium bromide/albuterol, one dose of ceftriaxone (1 g IV), and one dose of azithromycin (500 mg po). In the absence of significant leg edema and an elevation of jugular venous distention with a normal two-dimensional echocardiogram, heart failure was ruled out. The chest pains reported on initial presentation were ultimately felt to be noncardiac in nature.

After the patient was transferred to the medical floor with an initial diagnosis of exacerbation of her COPD, she was treated with antibiotics, nebulizers, and corticosteroids. She continued to experience episodes of O₂ desaturation while on 4 L to 6 L of oxygen via nasal cannula and on a venturi mask. She was then placed on a BiPAP device, set to 12/5, and 50% Fio₂ (fraction of inspired oxygen), which improved her oxygenation.

Her hypoxia prompted further radiographic studies. The resulting chest CT scan showed ground glass opacities located primarily in the upper lung areas, greater on the right than on the left side (see Figure 2). The radiologist suggested that the hypoxia was caused by an infection, but because the patient’s presenting symptoms were chronic in nature, drug-induced causes were considered as well. Amiodarone was discontinued.

Cardiology was consulted and agreed that stopping amiodarone was acceptable since the patient was in sinus rhythm at the time. The patient continued to take antibiotics and prednisone. Her symptoms slowly improved during hospitalization, and she required less oxygen. Based on the patient’s presentation, physical exam findings, imaging studies, and laboratory findings, amiodarone-induced pulmonary toxicity (APT) was diagnosed.

She was discharged home on supplemental oxygen at 4 L via cannula, a tapering dosage of prednisone, and metered-dose inhalers for fluticasone/salmeterol and tiotropium bromide. She also had outpatient appointments scheduled, one with the pulmonologist to follow up on her imaging studies and to manage the prednisone taper and the other with the cardiologist to manage her atrial fibrillation.

At pulmonology two months later, she had a chest x-ray (see Figure 3) and pulmonary function tests (PFTs). The patient reported feeling progressively better in the past month. Her dyspnea on exertion had improved, and she did not require supplemental oxygen anymore. She stopped smoking cigarettes.

The patient continued to use fluticasone/salmeterol but stopped tiotropium bromide. On physical exam, her O₂ saturation was 95% on room air, heart rhythm and rate were regular, and her lungs revealed very minimal crackles at the right base but were otherwise clear.

The plan specified continuing the prednisone taper. The patient was asked to call the office if she had any worsening shortness of breath, cough, and sputum production. She was also encouraged to continue refraining from smoking cigarettes. This patient had done very well, with near complete resolution of symptoms and a clear chest x-ray.

Continue reading for discussion... 

DISCUSSION

Amiodarone, a highly effective antiarrhythmic drug, is FDA approved for suppressing ventricular fibrillation and ventricular tachycardia. It is also used off-label as a second- or third-line choice for atrial fibrillation.¹

Standard of care requires that, prior to starting amiodarone therapy, patients have a baseline chest x-ray and PFTs with diffusing capacity performed. Thereafter, the patient should be monitored with annual chest x-rays, with one performed promptly if new symptoms develop. Serial PFTs have not offered any benefit for monitoring, but a decrease of more than 15% in total lung capacity or more than 20% in diffusing capacity from baseline is consistent with APT.²

Adverse effects, both cardiac and noncardiac, are common with amiodarone therapy. They include proarrhythmias, bradycardia, and heart block, as well as thyroid and liver dysfunctions; dermatologic conditions such as blue-gray discoloration of the skin and photosensitivity; neurologic effects such as ataxia, paresthesias, and tremor; ocular problems, including corneal microdeposits; gastrointestinal problems such as nausea, anorexia, and consti­pation; and lung problems such as pulmonary toxicity, pleural effusion, and pleural thickening.^3-6 Of these, pulmonary toxicity is the most severe and life threatening.⁷

APT, also known as amiodarone pneumonitis and amiodarone lung, typically manifests from a few months to a year and a half after treatment is commenced.⁶ APT can occur even after the drug is discontinued, because amiodarone has a very long elimination half-life of approximately 15 to 45 days and a tendency to concentrate in organs with high blood perfusion and in adipose tissues.⁸ Patients taking 400 mg/d for two months or longer or 200 mg/d for more than two years are considered at higher risk for APT.⁹ The severity of disease appears to correlate with the cumulative dose and length of treatment.¹⁰

Numerous risk factors for pulmonary toxicity have been reported, including high drug dosage, pre-existing lung disease, patient age, and prior surgery (see Table 1).¹¹ According to an analysis of a database of 237 patients, only age and duration of amiodarone therapy were significant risk factors for APT.⁹ Its incidence is not precisely known; reported rates range from 1% to 17%.^6,12,13

Presentation with such nonspecific symptoms as shortness of breath, nonproductive cough, fatigue, hypoxia, and general malaise is typical for many pulmonary and cardiac illnesses (see Table 2), making APT difficult to diagnose.¹⁴ Occasionally, rapid onset with progression to pneumonitis and respiratory failure masquerades as acute respiratory distress syndrome (ARDS).¹⁵

Notable, however, is that APT can manifest with nonproductive cough and dyspnea in 50% to 75% of cases. In addition, presenting symptoms will include fever (33% to 50% of cases) with associated malaise, fatigue, chest pain, and weight loss. In patients with APT, the physical exam usually reveals bilateral crackles on inspiration, but diffuse rales may be heard as well.¹¹

Laboratory studies are not very helpful in diagnosing APT. Patients may present with nonspecific elevated WBCs without eosinophilia and an elevated LDH level.¹¹ An elevated ESR may be detected before symptoms of APT manifest and can be present at the time of diagnosis.⁶

Imaging studies are far more helpful and specific in diagnosing APT. The typical chest x-ray shows bilateral patchy diffuse infiltrates.¹² CT of the chest is usually more revealing, demonstrating ground glass opacities in the periphery and subpleural thickening, especially where infiltrates are denser. This thickening may result in pleuritic chest pain.⁶

The right upper lobe is more often affected in these cases than the left lung.⁶ Numerous pulmonary nodules in the upper lobes are found rarely and can be confused with lung cancer. These nodules are likely the result of an accumulation of the drug in areas of previous inflammation; a lung mass should prompt the addition of APT in the differential.^2,16

APT is a diagnosis of exclusion, requiring clinical suspicion, drug history, imaging, and consideration of the differential. The presence of three or more clinical factors supports a diagnosis of APT (see Table 3).¹¹

Once APT is recognized, the first action is to have the patient stop taking amiodarone, followed by the administration of corticosteroids (eg, prednisone 40 to 60 mg/d¹¹) for four to 12 months.¹⁷ Patients, especially those with underlying lung disease, will typically require temporary oxygen supplementation until hypoxia resolves. Even after the drug has been discontinued, some patients experience worsening symptoms before they see improvement simply because the drug can persist in lung tissue for up to a year following cessation of therapy.⁶

If APT is diagnosed early, the prognosis is favorable. In one study, a significant number of APT patients stabilized or improved after withdrawal of the drug, regardless of concurrent treatment with corticosteroids.¹⁸ Follow-up studies, both imaging and PFT, indicate complete clearing of lung opacities in the majority of patients treated for APT.¹⁹ Radiologic improvement may be seen six months after cessation of amiodarone.²⁰ Patients who develop ARDS tend to do poorly and have a mortality rate of approximately 50%.¹¹

Continue reading for the conclusion...

CONCLUSION

Among patients who are taking long-term or high-dose amiodarone, particularly those older than 60, new-onset nonproductive cough and dyspnea signal the need for pulmonary and cardiac work-up. Once the diagnosis of APT is made, treatment is straightforward: Withdraw the amiodarone, and initiate corticosteroid therapy.

REFERENCES

1. Fuster V, Rydén LE, Asinger RW, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation); North American Society of Pacing and Electrophysiology. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. Circulation. 2001; 104(17):2118-2150.

2. Jarand J, Lee A, Leigh R. Amiodaronoma: an unusual form of amiodarone-induced pulmonary toxicity. CMAJ. 2007;176(10):1411-1413.

3. Connolly S. Evidence-based analysis of amiodarone efficacy and safety. Circulation. 1999;100:2025-2034.

4. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: meta-analysis of individual data from 6500 patients in randomised trials. Lancet. 1997;350(9089):1417-1424.

5. Pollak PT. Clinical organ toxicity of antiarrhythmic compounds: ocular and pulmonary manifestations. Am J Cardiol. 1999;84(9A):37R-45R.

6. Camus P, Martin W, Rosenow E. Amiodarone pulmonary toxicity. Clin Chest Med. 2004;25(1):65-75.

7. Rady MY, Ryan T, Starr NJ. Preoperative therapy with amiodarone and the incidence of acute organ dysfunction after cardiac surgery. Anesth Analg. 1997;85(3):489-497.

8. Canada A, Lesko L, Haffajee C, et al. Amiodarone for tachyarrhythmias: kinetics, and efficacy. Drug Intell Clin Pharm. 1983;17(2):100-104.

9. Ernawati DK, Stafford L, Hughes JD. Amiodarone-induced pulmonary toxicity. Br J Clin Pharmacol. 2008;66(1):82-87.

10. Liu FL, Cohen RD, Downar E, et al. Amiodarone pulmonary toxicity: functional and ultrastructural evaluation. Thorax. 1986;41(2):100-105.

11. Chan E, King TE. Amiodarone pulmonary toxicity. UpToDate. 2013. www.uptodate.com/contents/amiodarone-pulmonary-toxicity. Accessed January 17, 2014.

12. Wolkove N, Baltzan M. Amiodarone pulmonary toxicity. Can Respir J. 2009;16(2):43-48.

13. Jackevicius CA, Tom A, Essebag V, et al. Population-level incidence and risk factors for pulmonary toxicity associated with amiodarone. Am J Cardiol. 2011;108:705-710.

14. Jessurun G, Crijns H. Amiodarone pulmonary toxicity [editorial]. BMJ. 1997;314(7081):619-620.

15. Nacca N, Castigliano B, Yuhico L, et al. Severe amiodarone induced pulmonary toxicity. J Thorac Dis. 2012;4(6):667-670.

16. Arnon R, Raz I, Chajek-Shaul T, et al. Amiodarone pulmonary toxicity presenting as a solitary lung mass. Chest. 1988;93(2):425-427.

17. Yamada Y, Shiga T, Matsuda N, et al. Incidence and predictors of pulmonary toxicity in Japanese patients receiving low-dose amiodarone. Circ J. 2007;71(10):1610-1616.

18. Coudert B, Bailly F, Lombard JN, et al. Amiodarone pneumonitis: bronchoalveolar lavage findings in 15 patients and review of the literature. Chest. 1992;102(4):1005-1012.

19. Vernhet H, Bousquet C, Durand G, et al. Reversible amiodarone-induced lung disease: HRCT findings. Eur Radiol. 2001;11(9):1697-1703.

20. Olson LK, Forrest JV, Friedman PJ, et al. Pneumonitis after amiodarone therapy. Radiology. 1984;150(2):327-330.

Once again our authorities choose to agree rather than disagree. Although there may be some minor differences in opinion, it appears that both suggest that careful observation is the preferred management for small abdominal aortic aneurysms. However, there may still be some controversy since I believe the data they use to support observation is confounded by including patients whose aneurysms were less than 5 cm. I think almost everyone would agree that it is safe to monitor the <5 cm AAA. But what about the 5.2 cm in a small woman or a patient with chronic obstructive pulmonary disease or a strong family history of rupture or, for that matter, in any patient? If you have an opinion one way or another I invite you to send your comments to [email protected] for inclusion in a future edition of Vascular Specialist. In the meantime if you go to www.Vascularspecialistonline.com you can respond to our "Online Question of the Month" about the treatment of these small AAA.

--Dr. Russell Samson is the medical editor of Vascular Specialist.

Procedural risks remain an issue.

By Kenneth Ouriel, M.D.

Abdominal aortic aneurysms (AAA) are treated to prevent death from aneurysm rupture. Depending on the patient’s baseline medical status, however, the risks of the procedure itself may outweigh the risks of leaving the aneurysm untreated.¹ Endovascular aneurysm repair (EVAR), originally developed as a less invasive alternative to traditional open surgery,² has incompletely addressed this issue. While prospective randomized clinical trials demonstrated reduction in early morbidity and mortality with EVAR, early benefits have not translated into long-term survival benefit over open surgical repair.^3,4

Several studies have demonstrated improved results with EVAR when performed in patients with smaller aneurysms.^5,6 This observation may relate to the frequency of more challenging anatomy in larger aneurysms, with a higher frequency of shorter, larger diameter, angulated, and conical proximal aortic necks. While the potential benefit of repair in patients with larger aneurysms is greatest with respect to the prevention of rupture, some of this benefit may be offset by poorer long-term outcome. These results are only in part a function of complications related to the device, such as proximal endoleaks and migration. In addition, patients with larger aneurysms are slightly older and sicker than those with smaller aneurysms, accounting for an increased frequency of non-aneurysm related events.

Noting the less challenging aortic anatomy and younger, healthier characteristics of the subpopulation with smaller AAA, two randomized studies were organized to compare the results of early endovascular repair versus ultrasound or computed tomographic (CT) surveillance.⁷ The PIVOTAL trial enrolled 728 subjects with AAA between 4 and 5 cm in diameter, randomizing to either early EVAR with the AneuRx or Talent endografts or to ultrasound/CT imaging studies every 6 months. The perioperative mortality rate was 0.6% in the early EVAR group. Over a mean follow-up period of 20 months, there were no differences in all-cause mortality between the two groups, each with 15 deaths (4.1%). The primary endpoint of rupture or aneurysm-related death was similar in the two groups, with a hazard ratio of 0.99 in the early EVAR group. However, at 36 months almost 50% of the surveillance group underwent aneurysm repair for sac enlargement, the development of aneurysm-related symptoms, or patient choice. Interestingly, a follow-up economic substudy documented similar health care costs in the two treatment groups at 48 months of follow-up, even though 36.3% of the surveyed patients did not undergo repair.

A second study, the CEASAR trial, randomized 360 patients with AAA 4.1-5.4 cm in diameter to early EVAR with the Cook Zenith device or to serial ultrasound surveillance. After 4.5 years of follow-up, no significant difference was detected in the primary endpoint of all-cause mortality. The Kaplan-Meier estimates of all-cause mortality was 14.5% in the early repair group versus 10.1% in the surveillance group. Aneurysm-related mortality, aneurysm rupture, and major morbidity rates were similar. Like the PIVOTAL trial, the majority of subjects underwent delayed repair, with a frequency of 60% at 3-years and 85% at 4.5 years.

The findings of these two randomized studies suggest that there is no survival advantage to early EVAR in patients with smaller AAA. With the increasing use of statins, ACE inhibitors, and better overall medical management in patients with AAA, the rate of aneurysm enlargement and risk of rupture are quite low in patients with small AAA.⁸ While survival benefits have not been demonstrated, however, there appear to be few quantifiable disadvantages to early repair. Moreover, the long-term financial impact to the healthcare system appears to be similar when patients are treated early compared to surveillance with serial imaging studies,⁹ and patient quality of life may be improved with early EVAR.¹⁰ These observations suggest that the repair of smaller AAA should be individualized, based upon the particular clinical presentation and the wishes of a patient. The summary of available data suggests that either approach protects a patient from rupture and surveillance culminates in the eventual repair of the aneurysm in the majority of patients.

Dr. Ouriel is a vascular surgeon and president and CEO of Syntactx.

References

1. J Vasc Surg, 2012. 55(5): p. 1263-7.

2. J Vasc Interv Radiol, 2012. 23(7): p. 866-72; quiz 872.

3. J Endovasc Ther, 2012. 19(2): p. 182-92.

4. J Vasc Surg, 2012. 55(1): p. 33-40.

5. Ann Vasc Surg, 2012. 26(6): p. 860 e1-7.

6. J Vasc Interv Radiol, 2013. 24(1): p. 49-55

7. J Vasc Surg, 2012. 56(3): p. 630-6.

8. J Cardiovasc Surg (Torino), 2013. 1. Br J Surg 2007;94:702-8.

2. Semin Interv Cardiol 2000;5:3-6.

3. NEnglJMed 2010;362:1863-71.

4. JAMA 2009;302:1535-42.

5.. J Vasc Surg 2003;37:1206-12.

6. J Vasc Surg 2006;44:920-29; discussion 9-31.

7. J Vasc Surg 2010;51:1081-7.

8. EurJVascEndovascSurg 2011;41:2-10.

9. J Vasc Surg 2013;58:302-10.

10. Eur J Vasc Endovasc Surg 2011;41:324-31.

Small aneurysms should be left alone.

By Karl A. Illig, M.D.

The currently accepted recommendation to delay repair of abdominal aortic aneurysms until they reach 5-5.5 cm is based on the historical mortality and morbidity of open repair.1 Endovascular aneurysm repair (EVAR) has clearly been shown to reduce the risk of operation, perhaps by as much as two-thirds. Should we now change the threshold for aneurysm repair, especially if the patient is a candidate for EVAR?

There are many arguments to repair small aneurysms. However, the answer really depends upon empirical data. At least three major papers address this question. In the U.K. Small Aneurysm Trial, 1,090 patients with abdominal aortic aneurysms measuring 4.0-5.5 cm in diameter were randomized to undergo early elective open surgery versus ultrasonic surveillance.² There was an early survival disadvantage for those undergoing open surgery, as expected, but the curves evened out at 3 years or so, and no survival advantage occurred in either group, obviously favoring observation alone. Similarly, the ADAM group, pursuing the same protocol in 1,136 U.S. veterans, found the same thing, despite a low operative mortality of 2.7%. No advantage to early open repair could be seen.³

What of the situation after endovascular repair? The PIVOTAL trial, the lead author of which wrote the accompanying commentary, randomly assigned 728 patients with aneurysms measuring 4.0-5.0 cm to early endovascular repair with the Medtronic device versus ultrasonic surveillance.⁴ Aneurysm rupture or aneurysm-related death occurred in only two patients in each group (0.6%). The authors appropriately concluded that surveillance alone was equally as efficacious as early endovascular repair for patients with small aneurysms.

Finally, what of the arguments that, by waiting until the aneurysm is larger, you lose the window of opportunity for endovascular repair? We recently explored this in a cohort of 221 patients undergoing preoperative CT scanning for aneurysms of all sizes.⁵ With receiver operator curve analysis, a cutoff of 5.7 cm best differentiated those who were endovascular candidates from those who were not. Put another way, the rate of endovascular suitability hovered right around 80% until the aneurysm reached 6 cm, at which point it dropped off. In other words, waiting until the aneurysm reaches 5.5 cm doesn’t reduce the chance that a patient will be a candidate for EVAR.

There are many arguments for early intervention in small aneurysms. The concept that EVAR is safer than the procedure originally used to make the recommendation to wait until 5.5 cm is a valid point. However, empiric data still do not show any benefit for either open or endovascular repair as opposed to surveillance at sizes smaller than this. The operative mortality difference is only a couple of percentage points or so, and long-term survival appears to be identical after the initial risk has passed. This 2% or 3% early survival benefit does not seem to impart any long-term advantage, and long-term survival does not seem to be impaired by being a bit conservative. Until data come along that definitively show benefit for early repair, current guidelines remain valid.

Dr. Illig is the director of vascular surgery at USF Health, Tampa.

References:

1. J Vasc Surg 2009;50(8S):1S-49S.

2. Lancet 1998; 352:1649-55.

3. NEJM 2002; 346 (19): 1437-44.

4. J Vasc Surg 2010; 51:1081-7.

5. J Vasc Surg 2010;52:873-7.

Once again our authorities choose to agree rather than disagree. Although there may be some minor differences in opinion, it appears that both suggest that careful observation is the preferred management for small abdominal aortic aneurysms. However, there may still be some controversy since I believe the data they use to support observation is confounded by including patients whose aneurysms were less than 5 cm. I think almost everyone would agree that it is safe to monitor the <5 cm AAA. But what about the 5.2 cm in a small woman or a patient with chronic obstructive pulmonary disease or a strong family history of rupture or, for that matter, in any patient? If you have an opinion one way or another I invite you to send your comments to [email protected] for inclusion in a future edition of Vascular Specialist. In the meantime if you go to www.Vascularspecialistonline.com you can respond to our "Online Question of the Month" about the treatment of these small AAA.

--Dr. Russell Samson is the medical editor of Vascular Specialist.

Procedural risks remain an issue.

By Kenneth Ouriel, M.D.

Abdominal aortic aneurysms (AAA) are treated to prevent death from aneurysm rupture. Depending on the patient’s baseline medical status, however, the risks of the procedure itself may outweigh the risks of leaving the aneurysm untreated.¹ Endovascular aneurysm repair (EVAR), originally developed as a less invasive alternative to traditional open surgery,² has incompletely addressed this issue. While prospective randomized clinical trials demonstrated reduction in early morbidity and mortality with EVAR, early benefits have not translated into long-term survival benefit over open surgical repair.^3,4

Several studies have demonstrated improved results with EVAR when performed in patients with smaller aneurysms.^5,6 This observation may relate to the frequency of more challenging anatomy in larger aneurysms, with a higher frequency of shorter, larger diameter, angulated, and conical proximal aortic necks. While the potential benefit of repair in patients with larger aneurysms is greatest with respect to the prevention of rupture, some of this benefit may be offset by poorer long-term outcome. These results are only in part a function of complications related to the device, such as proximal endoleaks and migration. In addition, patients with larger aneurysms are slightly older and sicker than those with smaller aneurysms, accounting for an increased frequency of non-aneurysm related events.

Noting the less challenging aortic anatomy and younger, healthier characteristics of the subpopulation with smaller AAA, two randomized studies were organized to compare the results of early endovascular repair versus ultrasound or computed tomographic (CT) surveillance.⁷ The PIVOTAL trial enrolled 728 subjects with AAA between 4 and 5 cm in diameter, randomizing to either early EVAR with the AneuRx or Talent endografts or to ultrasound/CT imaging studies every 6 months. The perioperative mortality rate was 0.6% in the early EVAR group. Over a mean follow-up period of 20 months, there were no differences in all-cause mortality between the two groups, each with 15 deaths (4.1%). The primary endpoint of rupture or aneurysm-related death was similar in the two groups, with a hazard ratio of 0.99 in the early EVAR group. However, at 36 months almost 50% of the surveillance group underwent aneurysm repair for sac enlargement, the development of aneurysm-related symptoms, or patient choice. Interestingly, a follow-up economic substudy documented similar health care costs in the two treatment groups at 48 months of follow-up, even though 36.3% of the surveyed patients did not undergo repair.

A second study, the CEASAR trial, randomized 360 patients with AAA 4.1-5.4 cm in diameter to early EVAR with the Cook Zenith device or to serial ultrasound surveillance. After 4.5 years of follow-up, no significant difference was detected in the primary endpoint of all-cause mortality. The Kaplan-Meier estimates of all-cause mortality was 14.5% in the early repair group versus 10.1% in the surveillance group. Aneurysm-related mortality, aneurysm rupture, and major morbidity rates were similar. Like the PIVOTAL trial, the majority of subjects underwent delayed repair, with a frequency of 60% at 3-years and 85% at 4.5 years.

The findings of these two randomized studies suggest that there is no survival advantage to early EVAR in patients with smaller AAA. With the increasing use of statins, ACE inhibitors, and better overall medical management in patients with AAA, the rate of aneurysm enlargement and risk of rupture are quite low in patients with small AAA.⁸ While survival benefits have not been demonstrated, however, there appear to be few quantifiable disadvantages to early repair. Moreover, the long-term financial impact to the healthcare system appears to be similar when patients are treated early compared to surveillance with serial imaging studies,⁹ and patient quality of life may be improved with early EVAR.¹⁰ These observations suggest that the repair of smaller AAA should be individualized, based upon the particular clinical presentation and the wishes of a patient. The summary of available data suggests that either approach protects a patient from rupture and surveillance culminates in the eventual repair of the aneurysm in the majority of patients.

Dr. Ouriel is a vascular surgeon and president and CEO of Syntactx.

References

1. J Vasc Surg, 2012. 55(5): p. 1263-7.

2. J Vasc Interv Radiol, 2012. 23(7): p. 866-72; quiz 872.

3. J Endovasc Ther, 2012. 19(2): p. 182-92.

4. J Vasc Surg, 2012. 55(1): p. 33-40.

5. Ann Vasc Surg, 2012. 26(6): p. 860 e1-7.

6. J Vasc Interv Radiol, 2013. 24(1): p. 49-55

7. J Vasc Surg, 2012. 56(3): p. 630-6.

8. J Cardiovasc Surg (Torino), 2013. 1. Br J Surg 2007;94:702-8.

2. Semin Interv Cardiol 2000;5:3-6.

3. NEnglJMed 2010;362:1863-71.

4. JAMA 2009;302:1535-42.

5.. J Vasc Surg 2003;37:1206-12.

6. J Vasc Surg 2006;44:920-29; discussion 9-31.

7. J Vasc Surg 2010;51:1081-7.

8. EurJVascEndovascSurg 2011;41:2-10.

9. J Vasc Surg 2013;58:302-10.

10. Eur J Vasc Endovasc Surg 2011;41:324-31.

Small aneurysms should be left alone.

By Karl A. Illig, M.D.

The currently accepted recommendation to delay repair of abdominal aortic aneurysms until they reach 5-5.5 cm is based on the historical mortality and morbidity of open repair.1 Endovascular aneurysm repair (EVAR) has clearly been shown to reduce the risk of operation, perhaps by as much as two-thirds. Should we now change the threshold for aneurysm repair, especially if the patient is a candidate for EVAR?

There are many arguments to repair small aneurysms. However, the answer really depends upon empirical data. At least three major papers address this question. In the U.K. Small Aneurysm Trial, 1,090 patients with abdominal aortic aneurysms measuring 4.0-5.5 cm in diameter were randomized to undergo early elective open surgery versus ultrasonic surveillance.² There was an early survival disadvantage for those undergoing open surgery, as expected, but the curves evened out at 3 years or so, and no survival advantage occurred in either group, obviously favoring observation alone. Similarly, the ADAM group, pursuing the same protocol in 1,136 U.S. veterans, found the same thing, despite a low operative mortality of 2.7%. No advantage to early open repair could be seen.³

What of the situation after endovascular repair? The PIVOTAL trial, the lead author of which wrote the accompanying commentary, randomly assigned 728 patients with aneurysms measuring 4.0-5.0 cm to early endovascular repair with the Medtronic device versus ultrasonic surveillance.⁴ Aneurysm rupture or aneurysm-related death occurred in only two patients in each group (0.6%). The authors appropriately concluded that surveillance alone was equally as efficacious as early endovascular repair for patients with small aneurysms.

Finally, what of the arguments that, by waiting until the aneurysm is larger, you lose the window of opportunity for endovascular repair? We recently explored this in a cohort of 221 patients undergoing preoperative CT scanning for aneurysms of all sizes.⁵ With receiver operator curve analysis, a cutoff of 5.7 cm best differentiated those who were endovascular candidates from those who were not. Put another way, the rate of endovascular suitability hovered right around 80% until the aneurysm reached 6 cm, at which point it dropped off. In other words, waiting until the aneurysm reaches 5.5 cm doesn’t reduce the chance that a patient will be a candidate for EVAR.

There are many arguments for early intervention in small aneurysms. The concept that EVAR is safer than the procedure originally used to make the recommendation to wait until 5.5 cm is a valid point. However, empiric data still do not show any benefit for either open or endovascular repair as opposed to surveillance at sizes smaller than this. The operative mortality difference is only a couple of percentage points or so, and long-term survival appears to be identical after the initial risk has passed. This 2% or 3% early survival benefit does not seem to impart any long-term advantage, and long-term survival does not seem to be impaired by being a bit conservative. Until data come along that definitively show benefit for early repair, current guidelines remain valid.

Dr. Illig is the director of vascular surgery at USF Health, Tampa.

References:

1. J Vasc Surg 2009;50(8S):1S-49S.

2. Lancet 1998; 352:1649-55.

3. NEJM 2002; 346 (19): 1437-44.

4. J Vasc Surg 2010; 51:1081-7.

5. J Vasc Surg 2010;52:873-7.

Once again our authorities choose to agree rather than disagree. Although there may be some minor differences in opinion, it appears that both suggest that careful observation is the preferred management for small abdominal aortic aneurysms. However, there may still be some controversy since I believe the data they use to support observation is confounded by including patients whose aneurysms were less than 5 cm. I think almost everyone would agree that it is safe to monitor the <5 cm AAA. But what about the 5.2 cm in a small woman or a patient with chronic obstructive pulmonary disease or a strong family history of rupture or, for that matter, in any patient? If you have an opinion one way or another I invite you to send your comments to [email protected] for inclusion in a future edition of Vascular Specialist. In the meantime if you go to www.Vascularspecialistonline.com you can respond to our "Online Question of the Month" about the treatment of these small AAA.

--Dr. Russell Samson is the medical editor of Vascular Specialist.

Procedural risks remain an issue.

By Kenneth Ouriel, M.D.

Abdominal aortic aneurysms (AAA) are treated to prevent death from aneurysm rupture. Depending on the patient’s baseline medical status, however, the risks of the procedure itself may outweigh the risks of leaving the aneurysm untreated.¹ Endovascular aneurysm repair (EVAR), originally developed as a less invasive alternative to traditional open surgery,² has incompletely addressed this issue. While prospective randomized clinical trials demonstrated reduction in early morbidity and mortality with EVAR, early benefits have not translated into long-term survival benefit over open surgical repair.^3,4

Several studies have demonstrated improved results with EVAR when performed in patients with smaller aneurysms.^5,6 This observation may relate to the frequency of more challenging anatomy in larger aneurysms, with a higher frequency of shorter, larger diameter, angulated, and conical proximal aortic necks. While the potential benefit of repair in patients with larger aneurysms is greatest with respect to the prevention of rupture, some of this benefit may be offset by poorer long-term outcome. These results are only in part a function of complications related to the device, such as proximal endoleaks and migration. In addition, patients with larger aneurysms are slightly older and sicker than those with smaller aneurysms, accounting for an increased frequency of non-aneurysm related events.

Noting the less challenging aortic anatomy and younger, healthier characteristics of the subpopulation with smaller AAA, two randomized studies were organized to compare the results of early endovascular repair versus ultrasound or computed tomographic (CT) surveillance.⁷ The PIVOTAL trial enrolled 728 subjects with AAA between 4 and 5 cm in diameter, randomizing to either early EVAR with the AneuRx or Talent endografts or to ultrasound/CT imaging studies every 6 months. The perioperative mortality rate was 0.6% in the early EVAR group. Over a mean follow-up period of 20 months, there were no differences in all-cause mortality between the two groups, each with 15 deaths (4.1%). The primary endpoint of rupture or aneurysm-related death was similar in the two groups, with a hazard ratio of 0.99 in the early EVAR group. However, at 36 months almost 50% of the surveillance group underwent aneurysm repair for sac enlargement, the development of aneurysm-related symptoms, or patient choice. Interestingly, a follow-up economic substudy documented similar health care costs in the two treatment groups at 48 months of follow-up, even though 36.3% of the surveyed patients did not undergo repair.

A second study, the CEASAR trial, randomized 360 patients with AAA 4.1-5.4 cm in diameter to early EVAR with the Cook Zenith device or to serial ultrasound surveillance. After 4.5 years of follow-up, no significant difference was detected in the primary endpoint of all-cause mortality. The Kaplan-Meier estimates of all-cause mortality was 14.5% in the early repair group versus 10.1% in the surveillance group. Aneurysm-related mortality, aneurysm rupture, and major morbidity rates were similar. Like the PIVOTAL trial, the majority of subjects underwent delayed repair, with a frequency of 60% at 3-years and 85% at 4.5 years.

The findings of these two randomized studies suggest that there is no survival advantage to early EVAR in patients with smaller AAA. With the increasing use of statins, ACE inhibitors, and better overall medical management in patients with AAA, the rate of aneurysm enlargement and risk of rupture are quite low in patients with small AAA.⁸ While survival benefits have not been demonstrated, however, there appear to be few quantifiable disadvantages to early repair. Moreover, the long-term financial impact to the healthcare system appears to be similar when patients are treated early compared to surveillance with serial imaging studies,⁹ and patient quality of life may be improved with early EVAR.¹⁰ These observations suggest that the repair of smaller AAA should be individualized, based upon the particular clinical presentation and the wishes of a patient. The summary of available data suggests that either approach protects a patient from rupture and surveillance culminates in the eventual repair of the aneurysm in the majority of patients.

Dr. Ouriel is a vascular surgeon and president and CEO of Syntactx.

References

1. J Vasc Surg, 2012. 55(5): p. 1263-7.

2. J Vasc Interv Radiol, 2012. 23(7): p. 866-72; quiz 872.

3. J Endovasc Ther, 2012. 19(2): p. 182-92.

4. J Vasc Surg, 2012. 55(1): p. 33-40.

5. Ann Vasc Surg, 2012. 26(6): p. 860 e1-7.

6. J Vasc Interv Radiol, 2013. 24(1): p. 49-55

7. J Vasc Surg, 2012. 56(3): p. 630-6.

8. J Cardiovasc Surg (Torino), 2013. 1. Br J Surg 2007;94:702-8.

2. Semin Interv Cardiol 2000;5:3-6.

3. NEnglJMed 2010;362:1863-71.

4. JAMA 2009;302:1535-42.

5.. J Vasc Surg 2003;37:1206-12.

6. J Vasc Surg 2006;44:920-29; discussion 9-31.

7. J Vasc Surg 2010;51:1081-7.

8. EurJVascEndovascSurg 2011;41:2-10.

9. J Vasc Surg 2013;58:302-10.

10. Eur J Vasc Endovasc Surg 2011;41:324-31.

Small aneurysms should be left alone.

By Karl A. Illig, M.D.

The currently accepted recommendation to delay repair of abdominal aortic aneurysms until they reach 5-5.5 cm is based on the historical mortality and morbidity of open repair.1 Endovascular aneurysm repair (EVAR) has clearly been shown to reduce the risk of operation, perhaps by as much as two-thirds. Should we now change the threshold for aneurysm repair, especially if the patient is a candidate for EVAR?

There are many arguments to repair small aneurysms. However, the answer really depends upon empirical data. At least three major papers address this question. In the U.K. Small Aneurysm Trial, 1,090 patients with abdominal aortic aneurysms measuring 4.0-5.5 cm in diameter were randomized to undergo early elective open surgery versus ultrasonic surveillance.² There was an early survival disadvantage for those undergoing open surgery, as expected, but the curves evened out at 3 years or so, and no survival advantage occurred in either group, obviously favoring observation alone. Similarly, the ADAM group, pursuing the same protocol in 1,136 U.S. veterans, found the same thing, despite a low operative mortality of 2.7%. No advantage to early open repair could be seen.³

What of the situation after endovascular repair? The PIVOTAL trial, the lead author of which wrote the accompanying commentary, randomly assigned 728 patients with aneurysms measuring 4.0-5.0 cm to early endovascular repair with the Medtronic device versus ultrasonic surveillance.⁴ Aneurysm rupture or aneurysm-related death occurred in only two patients in each group (0.6%). The authors appropriately concluded that surveillance alone was equally as efficacious as early endovascular repair for patients with small aneurysms.

Finally, what of the arguments that, by waiting until the aneurysm is larger, you lose the window of opportunity for endovascular repair? We recently explored this in a cohort of 221 patients undergoing preoperative CT scanning for aneurysms of all sizes.⁵ With receiver operator curve analysis, a cutoff of 5.7 cm best differentiated those who were endovascular candidates from those who were not. Put another way, the rate of endovascular suitability hovered right around 80% until the aneurysm reached 6 cm, at which point it dropped off. In other words, waiting until the aneurysm reaches 5.5 cm doesn’t reduce the chance that a patient will be a candidate for EVAR.

There are many arguments for early intervention in small aneurysms. The concept that EVAR is safer than the procedure originally used to make the recommendation to wait until 5.5 cm is a valid point. However, empiric data still do not show any benefit for either open or endovascular repair as opposed to surveillance at sizes smaller than this. The operative mortality difference is only a couple of percentage points or so, and long-term survival appears to be identical after the initial risk has passed. This 2% or 3% early survival benefit does not seem to impart any long-term advantage, and long-term survival does not seem to be impaired by being a bit conservative. Until data come along that definitively show benefit for early repair, current guidelines remain valid.

Dr. Illig is the director of vascular surgery at USF Health, Tampa.

References:

1. J Vasc Surg 2009;50(8S):1S-49S.

2. Lancet 1998; 352:1649-55.

3. NEJM 2002; 346 (19): 1437-44.

4. J Vasc Surg 2010; 51:1081-7.

5. J Vasc Surg 2010;52:873-7.

Alcohol consumption may reduce the risk of developing multiple sclerosis (MS) and attenuate the effect of smoking, according to research published online ahead of print January 6 in JAMA Neurology. Scientists examined data from the Epidemiological Investigation of MS (EIMS), which included 745 cases and 1,761 controls, and from the Genes and Environment in MS (GEMS) study, which recruited 5,874 cases and 5,246 controls. In EIMS, women who reported high alcohol consumption (>112 g/week) had an odds ratio (OR) of 0.6 of developing MS, compared with nondrinking women. Men with high alcohol consumption (>168 g/week) in EIMS had an OR of 0.5, compared with nondrinking men. The OR for the comparison in GEMS was 0.7 for women and 0.7 for men. In both studies, the detrimental effect of smoking was more pronounced among nondrinkers.

A lentiviral vector-based gene therapy may be safe and improve motor behavior in patients with Parkinson’s disease, according to a study published online ahead of print January 10 in Lancet. In a phase I–II open-label trial, 15 patients received bilateral injections of gene therapy into the putamen and were followed up for 12 months. Participants received a low dose (1.9 × 107 transducing units [TU]), medium dose (4.0 × 107 TU), or a high dose (1 × 108 TU) of gene therapy. Patients reported 51 mild adverse events, three moderate adverse events, and no serious adverse events. The investigators noted a significant improvement in mean Unified Parkinson’s Disease Rating Scale part III motor scores off medication in all patients at six months, compared with baseline.

The FDA has approved a three-times-per-week formulation of Copaxone 40 mg/mL. The new formulation will enable a less-frequent dosing regimen to be administered subcutaneously to patients with relapsing forms of multiple sclerosis (MS). The approval is based on data from the Phase III Glatiramer Acetate Low-Frequency Administration study of more than 1,400 patients. In the trial, investigators found that a 40-mg/mL dose of Copaxone administered subcutaneously three times per week significantly reduced relapse rates at 12 months and demonstrated a favorable safety and tolerability profile in patients with relapsing-remitting MS. In addition to the newly approved dose, daily Copaxone 20 mg/mL will continue to be available. The daily subcutaneous injection was approved in 1996. Both formulations are manufactured by Teva Pharmaceutical Industries, which is headquartered in Jerusalem.

When administered with amitriptyline, cognitive behavioral therapy (CBT) may result in greater reductions in days with headache and in migraine-related disability among young persons with chronic migraine, compared with headache education, according to research published December 25, 2013, in JAMA. In a randomized clinical trial, 135 children (ages 10 to 17) with chronic migraine and a Pediatric Migraine Disability Assessment Score (PedMIDAS) greater than 20 points were assigned to CBT plus amitriptyline or headache education plus amitriptyline. At the 20-week end point, days with headache were reduced by 11.5 for the CBT plus amitriptyline group, compared with 6.8 for the headache education plus amitriptyline group. The PedMIDAS decreased by 52.7 points for the CBT group and by 38.6 points for the headache education group.

Low levels of vitamin D early in the course of multiple sclerosis (MS) are a strong risk factor for long-term disease activity and progression in patients who were primarily treated with interferon beta-1b, according to a study published online January 20 in JAMA Neurology. Researchers compared early and delayed interferon beta-1b treatment in 468 patients with clinically isolated syndrome, measuring serum levels of 25-hydroxyvitamin D (25[OH]D) at baseline and at six, 12, and 24 months. “A 50-nmol/L (20-ng/mL) increment in average serum 25(OH)D levels within the first 12 months predicted a 57% lower rate of new active lesions, 57% lower relapse rate, 25% lower yearly increase in T2 lesion volume, and 0.41% lower yearly loss in brain volume from months 12 to 60,” stated the study authors.

Excessive alcohol consumption in men was associated with faster cognitive decline, compared with light to moderate alcohol consumption, researchers reported online ahead of print January 15 in Neurology. The findings are based on data from 5,054 men and 2,099 women (mean age, 56) who had their alcohol consumption analyzed three times in the 10 years preceding the first cognitive assessment. In men, the investigators observed no differences in cognitive decline among alcohol abstainers, those who quit using alcohol, and light or moderate alcohol drinkers (<20 g/day). Alcohol consumption ≥36 g/day was associated with faster decline in all cognitive domains, compared with consumption between 0.1 and 19.9 g/day. In women, 10-year abstainers had a faster decline in the global cognitive score and executive function, compared with those drinking between 0.1 and 9.9 g/day of alcohol.

Vitamin D supplements may reduce pain in patients with fibromyalgia syndrome, according to a study in the February issue of Pain. The randomized controlled trial enrolled 30 women with fibromyalgia syndrome with serum calcifediol levels <32 ng/mL (80 nmol/L), in whom the goal was to achieve serum calcifediol levels between 32 and 48 ng/mL for 20 weeks with an oral cholecalciferol supplement. Re-evaluation was performed in both groups after an additional 24 weeks without cholecalciferol supplementation. The researchers observed a marked reduction in pain during the treatment period in those who received the supplement, and optimization of calcifediol levels had a positive effect on the perception of pain. “This economical therapy with a low side effect profile may well be considered in patients with fibromyalgia syndrome,” the researchers concluded.

A simple on-field blood test may help diagnose sports concussion. Relative and absolute increases in the astroglial protein, serum S100B, can accurately distinguish sports-related concussion from sports-related exertion, according to a study published online January 8 in PLOS One. Serum S100B was measured in 46 collegiate and semiprofessional contact sport athletes at preseason baseline, within three hours of injury, and at days 2, 3, and 7 post–sports-related concussion. Twenty-two athletes had a sports-related concussion, and 17 had S100B testing within three hours postinjury. The mean three-hour post–sports-related concussion S100B level was significantly higher than at preseason baseline, while the mean postexertion S100B level was not significantly different than that from the preseason baseline. S100B levels at postinjury days 2, 3, and 7 were significantly lower than at the three-hour level and were not different than at baseline.

Herpes zoster is an independent risk factor for vascular disease, particularly for stroke, transient ischemic attack, and myocardial infarction, in patients affected before age 40, researchers reported online ahead of print January 2 in Neurology. The findings are based on a retrospective cohort of 106,601 cases of herpes zoster and 213,202 controls from a general practice database in the United Kingdom. The investigators found that risk factors for vascular disease were significantly increased in patients with herpes zoster compared with controls. In addition, adjusted hazard ratios for TIA and myocardial infarction, but not stroke, were increased in all patients with herpes zoster. Stroke, TIA, and myocardial infarction were increased in cases in which herpes zoster occurred when the participants were younger than 40.

A study appearing January 22 online in Neurology found that a higher omega-3 index was correlated with larger total normal brain volume and hippocampal volume in postmenopausal women measured eight years later. Researchers assessed RBC eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and MRI brain volumes in 1,111 postmenopausal women from the Women’s Health Initiative Memory Study. In fully adjusted models, a 1-SD greater RBC EPA + DHA (omega-3 index) level was correlated with 2.1 cm3 larger brain volume. “DHA was marginally correlated with total brain volume while EPA was less so,” reported the investigators. In fully adjusted models, a 1-SD greater omega-3 index was correlated with greater hippocampal volume. “While normal aging results in overall brain atrophy, lower omega-3 index may signal increased risk of hippocampal atrophy,” wrote the investigators.

Exposure to DDT may increase the risk of developing Alzheimer’s disease, particularly in people older than 60, according to a study published online ahead of print January 27 in JAMA Neurology. Researchers examined the level of DDE, the chemical compound produced when DDT breaks down in the body, in the blood of 86 patients with Alzheimer’s disease and 79 controls. Blood levels of DDE were almost four times higher in 74 of the patients with Alzheimer’s disease than in the controls. Patients with APOE4, which greatly increases the risk of developing Alzheimer’s disease, and high blood levels of DDE exhibited more severe cognitive impairment than patients without the gene. In addition, DDT and DDE apparently increased the amount of a protein associated with plaques believed to be a hallmark of Alzheimer’s disease.

Mortality is higher among patients with multiple sclerosis (MS) than among Americans without the disease, according to research published online ahead of print December 26, 2013, in Multiple Sclerosis and Related Disorders. Investigators extracted records from a US commercial health insurance database—the OptumInsight Research database—for 30,402 patients with MS and 89,818 healthy comparators. Patient data were recorded from 1996 to 2009. Annual mortality rates were 899/100,000 among patients with MS and 446/100,000 among comparators. Standardized mortality ratio was 1.70 for patients with MS and 0.80 for the general US population. Kaplan–Meier analysis yielded a median survival from birth that was six years lower among patients with MS than among comparators. The six-year decrement in lifespan is consistent with a decrement found in recent research conducted in Canada, said the investigators.

Chronic obstructive pulmonary disease (COPD) may increase the risk of mild cognitive impairment (MCI), researchers reported in the November 2013 issue of Mayo Clinic Proceedings. The investigators evaluated 1,927 patients (ages 70 to 89) enrolled in the population-based Mayo Clinic Study of Aging. Participants received a nurse assessment, neurologic evaluation, and neuropsychologic testing. A consensus panel diagnosed MCI according to standardized criteria. COPD was identified by the review of medical records. A total of 288 patients had COPD. Prevalence of MCI was 27% among patients with COPD and 15% among patients without COPD. The odds ratio for MCI was 1.60 in patients who had had COPD for five years or fewer and 2.10 in patients who had had COPD for more than five years.

—Erik Greb and Colby Stong

Alcohol consumption may reduce the risk of developing multiple sclerosis (MS) and attenuate the effect of smoking, according to research published online ahead of print January 6 in JAMA Neurology. Scientists examined data from the Epidemiological Investigation of MS (EIMS), which included 745 cases and 1,761 controls, and from the Genes and Environment in MS (GEMS) study, which recruited 5,874 cases and 5,246 controls. In EIMS, women who reported high alcohol consumption (>112 g/week) had an odds ratio (OR) of 0.6 of developing MS, compared with nondrinking women. Men with high alcohol consumption (>168 g/week) in EIMS had an OR of 0.5, compared with nondrinking men. The OR for the comparison in GEMS was 0.7 for women and 0.7 for men. In both studies, the detrimental effect of smoking was more pronounced among nondrinkers.

A lentiviral vector-based gene therapy may be safe and improve motor behavior in patients with Parkinson’s disease, according to a study published online ahead of print January 10 in Lancet. In a phase I–II open-label trial, 15 patients received bilateral injections of gene therapy into the putamen and were followed up for 12 months. Participants received a low dose (1.9 × 107 transducing units [TU]), medium dose (4.0 × 107 TU), or a high dose (1 × 108 TU) of gene therapy. Patients reported 51 mild adverse events, three moderate adverse events, and no serious adverse events. The investigators noted a significant improvement in mean Unified Parkinson’s Disease Rating Scale part III motor scores off medication in all patients at six months, compared with baseline.

The FDA has approved a three-times-per-week formulation of Copaxone 40 mg/mL. The new formulation will enable a less-frequent dosing regimen to be administered subcutaneously to patients with relapsing forms of multiple sclerosis (MS). The approval is based on data from the Phase III Glatiramer Acetate Low-Frequency Administration study of more than 1,400 patients. In the trial, investigators found that a 40-mg/mL dose of Copaxone administered subcutaneously three times per week significantly reduced relapse rates at 12 months and demonstrated a favorable safety and tolerability profile in patients with relapsing-remitting MS. In addition to the newly approved dose, daily Copaxone 20 mg/mL will continue to be available. The daily subcutaneous injection was approved in 1996. Both formulations are manufactured by Teva Pharmaceutical Industries, which is headquartered in Jerusalem.

When administered with amitriptyline, cognitive behavioral therapy (CBT) may result in greater reductions in days with headache and in migraine-related disability among young persons with chronic migraine, compared with headache education, according to research published December 25, 2013, in JAMA. In a randomized clinical trial, 135 children (ages 10 to 17) with chronic migraine and a Pediatric Migraine Disability Assessment Score (PedMIDAS) greater than 20 points were assigned to CBT plus amitriptyline or headache education plus amitriptyline. At the 20-week end point, days with headache were reduced by 11.5 for the CBT plus amitriptyline group, compared with 6.8 for the headache education plus amitriptyline group. The PedMIDAS decreased by 52.7 points for the CBT group and by 38.6 points for the headache education group.

Low levels of vitamin D early in the course of multiple sclerosis (MS) are a strong risk factor for long-term disease activity and progression in patients who were primarily treated with interferon beta-1b, according to a study published online January 20 in JAMA Neurology. Researchers compared early and delayed interferon beta-1b treatment in 468 patients with clinically isolated syndrome, measuring serum levels of 25-hydroxyvitamin D (25[OH]D) at baseline and at six, 12, and 24 months. “A 50-nmol/L (20-ng/mL) increment in average serum 25(OH)D levels within the first 12 months predicted a 57% lower rate of new active lesions, 57% lower relapse rate, 25% lower yearly increase in T2 lesion volume, and 0.41% lower yearly loss in brain volume from months 12 to 60,” stated the study authors.

Excessive alcohol consumption in men was associated with faster cognitive decline, compared with light to moderate alcohol consumption, researchers reported online ahead of print January 15 in Neurology. The findings are based on data from 5,054 men and 2,099 women (mean age, 56) who had their alcohol consumption analyzed three times in the 10 years preceding the first cognitive assessment. In men, the investigators observed no differences in cognitive decline among alcohol abstainers, those who quit using alcohol, and light or moderate alcohol drinkers (<20 g/day). Alcohol consumption ≥36 g/day was associated with faster decline in all cognitive domains, compared with consumption between 0.1 and 19.9 g/day. In women, 10-year abstainers had a faster decline in the global cognitive score and executive function, compared with those drinking between 0.1 and 9.9 g/day of alcohol.

Vitamin D supplements may reduce pain in patients with fibromyalgia syndrome, according to a study in the February issue of Pain. The randomized controlled trial enrolled 30 women with fibromyalgia syndrome with serum calcifediol levels <32 ng/mL (80 nmol/L), in whom the goal was to achieve serum calcifediol levels between 32 and 48 ng/mL for 20 weeks with an oral cholecalciferol supplement. Re-evaluation was performed in both groups after an additional 24 weeks without cholecalciferol supplementation. The researchers observed a marked reduction in pain during the treatment period in those who received the supplement, and optimization of calcifediol levels had a positive effect on the perception of pain. “This economical therapy with a low side effect profile may well be considered in patients with fibromyalgia syndrome,” the researchers concluded.

A simple on-field blood test may help diagnose sports concussion. Relative and absolute increases in the astroglial protein, serum S100B, can accurately distinguish sports-related concussion from sports-related exertion, according to a study published online January 8 in PLOS One. Serum S100B was measured in 46 collegiate and semiprofessional contact sport athletes at preseason baseline, within three hours of injury, and at days 2, 3, and 7 post–sports-related concussion. Twenty-two athletes had a sports-related concussion, and 17 had S100B testing within three hours postinjury. The mean three-hour post–sports-related concussion S100B level was significantly higher than at preseason baseline, while the mean postexertion S100B level was not significantly different than that from the preseason baseline. S100B levels at postinjury days 2, 3, and 7 were significantly lower than at the three-hour level and were not different than at baseline.

Herpes zoster is an independent risk factor for vascular disease, particularly for stroke, transient ischemic attack, and myocardial infarction, in patients affected before age 40, researchers reported online ahead of print January 2 in Neurology. The findings are based on a retrospective cohort of 106,601 cases of herpes zoster and 213,202 controls from a general practice database in the United Kingdom. The investigators found that risk factors for vascular disease were significantly increased in patients with herpes zoster compared with controls. In addition, adjusted hazard ratios for TIA and myocardial infarction, but not stroke, were increased in all patients with herpes zoster. Stroke, TIA, and myocardial infarction were increased in cases in which herpes zoster occurred when the participants were younger than 40.

A study appearing January 22 online in Neurology found that a higher omega-3 index was correlated with larger total normal brain volume and hippocampal volume in postmenopausal women measured eight years later. Researchers assessed RBC eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and MRI brain volumes in 1,111 postmenopausal women from the Women’s Health Initiative Memory Study. In fully adjusted models, a 1-SD greater RBC EPA + DHA (omega-3 index) level was correlated with 2.1 cm3 larger brain volume. “DHA was marginally correlated with total brain volume while EPA was less so,” reported the investigators. In fully adjusted models, a 1-SD greater omega-3 index was correlated with greater hippocampal volume. “While normal aging results in overall brain atrophy, lower omega-3 index may signal increased risk of hippocampal atrophy,” wrote the investigators.

Exposure to DDT may increase the risk of developing Alzheimer’s disease, particularly in people older than 60, according to a study published online ahead of print January 27 in JAMA Neurology. Researchers examined the level of DDE, the chemical compound produced when DDT breaks down in the body, in the blood of 86 patients with Alzheimer’s disease and 79 controls. Blood levels of DDE were almost four times higher in 74 of the patients with Alzheimer’s disease than in the controls. Patients with APOE4, which greatly increases the risk of developing Alzheimer’s disease, and high blood levels of DDE exhibited more severe cognitive impairment than patients without the gene. In addition, DDT and DDE apparently increased the amount of a protein associated with plaques believed to be a hallmark of Alzheimer’s disease.

Mortality is higher among patients with multiple sclerosis (MS) than among Americans without the disease, according to research published online ahead of print December 26, 2013, in Multiple Sclerosis and Related Disorders. Investigators extracted records from a US commercial health insurance database—the OptumInsight Research database—for 30,402 patients with MS and 89,818 healthy comparators. Patient data were recorded from 1996 to 2009. Annual mortality rates were 899/100,000 among patients with MS and 446/100,000 among comparators. Standardized mortality ratio was 1.70 for patients with MS and 0.80 for the general US population. Kaplan–Meier analysis yielded a median survival from birth that was six years lower among patients with MS than among comparators. The six-year decrement in lifespan is consistent with a decrement found in recent research conducted in Canada, said the investigators.

Chronic obstructive pulmonary disease (COPD) may increase the risk of mild cognitive impairment (MCI), researchers reported in the November 2013 issue of Mayo Clinic Proceedings. The investigators evaluated 1,927 patients (ages 70 to 89) enrolled in the population-based Mayo Clinic Study of Aging. Participants received a nurse assessment, neurologic evaluation, and neuropsychologic testing. A consensus panel diagnosed MCI according to standardized criteria. COPD was identified by the review of medical records. A total of 288 patients had COPD. Prevalence of MCI was 27% among patients with COPD and 15% among patients without COPD. The odds ratio for MCI was 1.60 in patients who had had COPD for five years or fewer and 2.10 in patients who had had COPD for more than five years.

—Erik Greb and Colby Stong

Alcohol consumption may reduce the risk of developing multiple sclerosis (MS) and attenuate the effect of smoking, according to research published online ahead of print January 6 in JAMA Neurology. Scientists examined data from the Epidemiological Investigation of MS (EIMS), which included 745 cases and 1,761 controls, and from the Genes and Environment in MS (GEMS) study, which recruited 5,874 cases and 5,246 controls. In EIMS, women who reported high alcohol consumption (>112 g/week) had an odds ratio (OR) of 0.6 of developing MS, compared with nondrinking women. Men with high alcohol consumption (>168 g/week) in EIMS had an OR of 0.5, compared with nondrinking men. The OR for the comparison in GEMS was 0.7 for women and 0.7 for men. In both studies, the detrimental effect of smoking was more pronounced among nondrinkers.

A lentiviral vector-based gene therapy may be safe and improve motor behavior in patients with Parkinson’s disease, according to a study published online ahead of print January 10 in Lancet. In a phase I–II open-label trial, 15 patients received bilateral injections of gene therapy into the putamen and were followed up for 12 months. Participants received a low dose (1.9 × 107 transducing units [TU]), medium dose (4.0 × 107 TU), or a high dose (1 × 108 TU) of gene therapy. Patients reported 51 mild adverse events, three moderate adverse events, and no serious adverse events. The investigators noted a significant improvement in mean Unified Parkinson’s Disease Rating Scale part III motor scores off medication in all patients at six months, compared with baseline.

The FDA has approved a three-times-per-week formulation of Copaxone 40 mg/mL. The new formulation will enable a less-frequent dosing regimen to be administered subcutaneously to patients with relapsing forms of multiple sclerosis (MS). The approval is based on data from the Phase III Glatiramer Acetate Low-Frequency Administration study of more than 1,400 patients. In the trial, investigators found that a 40-mg/mL dose of Copaxone administered subcutaneously three times per week significantly reduced relapse rates at 12 months and demonstrated a favorable safety and tolerability profile in patients with relapsing-remitting MS. In addition to the newly approved dose, daily Copaxone 20 mg/mL will continue to be available. The daily subcutaneous injection was approved in 1996. Both formulations are manufactured by Teva Pharmaceutical Industries, which is headquartered in Jerusalem.

When administered with amitriptyline, cognitive behavioral therapy (CBT) may result in greater reductions in days with headache and in migraine-related disability among young persons with chronic migraine, compared with headache education, according to research published December 25, 2013, in JAMA. In a randomized clinical trial, 135 children (ages 10 to 17) with chronic migraine and a Pediatric Migraine Disability Assessment Score (PedMIDAS) greater than 20 points were assigned to CBT plus amitriptyline or headache education plus amitriptyline. At the 20-week end point, days with headache were reduced by 11.5 for the CBT plus amitriptyline group, compared with 6.8 for the headache education plus amitriptyline group. The PedMIDAS decreased by 52.7 points for the CBT group and by 38.6 points for the headache education group.

Low levels of vitamin D early in the course of multiple sclerosis (MS) are a strong risk factor for long-term disease activity and progression in patients who were primarily treated with interferon beta-1b, according to a study published online January 20 in JAMA Neurology. Researchers compared early and delayed interferon beta-1b treatment in 468 patients with clinically isolated syndrome, measuring serum levels of 25-hydroxyvitamin D (25[OH]D) at baseline and at six, 12, and 24 months. “A 50-nmol/L (20-ng/mL) increment in average serum 25(OH)D levels within the first 12 months predicted a 57% lower rate of new active lesions, 57% lower relapse rate, 25% lower yearly increase in T2 lesion volume, and 0.41% lower yearly loss in brain volume from months 12 to 60,” stated the study authors.

Excessive alcohol consumption in men was associated with faster cognitive decline, compared with light to moderate alcohol consumption, researchers reported online ahead of print January 15 in Neurology. The findings are based on data from 5,054 men and 2,099 women (mean age, 56) who had their alcohol consumption analyzed three times in the 10 years preceding the first cognitive assessment. In men, the investigators observed no differences in cognitive decline among alcohol abstainers, those who quit using alcohol, and light or moderate alcohol drinkers (<20 g/day). Alcohol consumption ≥36 g/day was associated with faster decline in all cognitive domains, compared with consumption between 0.1 and 19.9 g/day. In women, 10-year abstainers had a faster decline in the global cognitive score and executive function, compared with those drinking between 0.1 and 9.9 g/day of alcohol.

Vitamin D supplements may reduce pain in patients with fibromyalgia syndrome, according to a study in the February issue of Pain. The randomized controlled trial enrolled 30 women with fibromyalgia syndrome with serum calcifediol levels <32 ng/mL (80 nmol/L), in whom the goal was to achieve serum calcifediol levels between 32 and 48 ng/mL for 20 weeks with an oral cholecalciferol supplement. Re-evaluation was performed in both groups after an additional 24 weeks without cholecalciferol supplementation. The researchers observed a marked reduction in pain during the treatment period in those who received the supplement, and optimization of calcifediol levels had a positive effect on the perception of pain. “This economical therapy with a low side effect profile may well be considered in patients with fibromyalgia syndrome,” the researchers concluded.

A simple on-field blood test may help diagnose sports concussion. Relative and absolute increases in the astroglial protein, serum S100B, can accurately distinguish sports-related concussion from sports-related exertion, according to a study published online January 8 in PLOS One. Serum S100B was measured in 46 collegiate and semiprofessional contact sport athletes at preseason baseline, within three hours of injury, and at days 2, 3, and 7 post–sports-related concussion. Twenty-two athletes had a sports-related concussion, and 17 had S100B testing within three hours postinjury. The mean three-hour post–sports-related concussion S100B level was significantly higher than at preseason baseline, while the mean postexertion S100B level was not significantly different than that from the preseason baseline. S100B levels at postinjury days 2, 3, and 7 were significantly lower than at the three-hour level and were not different than at baseline.

Herpes zoster is an independent risk factor for vascular disease, particularly for stroke, transient ischemic attack, and myocardial infarction, in patients affected before age 40, researchers reported online ahead of print January 2 in Neurology. The findings are based on a retrospective cohort of 106,601 cases of herpes zoster and 213,202 controls from a general practice database in the United Kingdom. The investigators found that risk factors for vascular disease were significantly increased in patients with herpes zoster compared with controls. In addition, adjusted hazard ratios for TIA and myocardial infarction, but not stroke, were increased in all patients with herpes zoster. Stroke, TIA, and myocardial infarction were increased in cases in which herpes zoster occurred when the participants were younger than 40.

A study appearing January 22 online in Neurology found that a higher omega-3 index was correlated with larger total normal brain volume and hippocampal volume in postmenopausal women measured eight years later. Researchers assessed RBC eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and MRI brain volumes in 1,111 postmenopausal women from the Women’s Health Initiative Memory Study. In fully adjusted models, a 1-SD greater RBC EPA + DHA (omega-3 index) level was correlated with 2.1 cm3 larger brain volume. “DHA was marginally correlated with total brain volume while EPA was less so,” reported the investigators. In fully adjusted models, a 1-SD greater omega-3 index was correlated with greater hippocampal volume. “While normal aging results in overall brain atrophy, lower omega-3 index may signal increased risk of hippocampal atrophy,” wrote the investigators.

Exposure to DDT may increase the risk of developing Alzheimer’s disease, particularly in people older than 60, according to a study published online ahead of print January 27 in JAMA Neurology. Researchers examined the level of DDE, the chemical compound produced when DDT breaks down in the body, in the blood of 86 patients with Alzheimer’s disease and 79 controls. Blood levels of DDE were almost four times higher in 74 of the patients with Alzheimer’s disease than in the controls. Patients with APOE4, which greatly increases the risk of developing Alzheimer’s disease, and high blood levels of DDE exhibited more severe cognitive impairment than patients without the gene. In addition, DDT and DDE apparently increased the amount of a protein associated with plaques believed to be a hallmark of Alzheimer’s disease.

Mortality is higher among patients with multiple sclerosis (MS) than among Americans without the disease, according to research published online ahead of print December 26, 2013, in Multiple Sclerosis and Related Disorders. Investigators extracted records from a US commercial health insurance database—the OptumInsight Research database—for 30,402 patients with MS and 89,818 healthy comparators. Patient data were recorded from 1996 to 2009. Annual mortality rates were 899/100,000 among patients with MS and 446/100,000 among comparators. Standardized mortality ratio was 1.70 for patients with MS and 0.80 for the general US population. Kaplan–Meier analysis yielded a median survival from birth that was six years lower among patients with MS than among comparators. The six-year decrement in lifespan is consistent with a decrement found in recent research conducted in Canada, said the investigators.

Chronic obstructive pulmonary disease (COPD) may increase the risk of mild cognitive impairment (MCI), researchers reported in the November 2013 issue of Mayo Clinic Proceedings. The investigators evaluated 1,927 patients (ages 70 to 89) enrolled in the population-based Mayo Clinic Study of Aging. Participants received a nurse assessment, neurologic evaluation, and neuropsychologic testing. A consensus panel diagnosed MCI according to standardized criteria. COPD was identified by the review of medical records. A total of 288 patients had COPD. Prevalence of MCI was 27% among patients with COPD and 15% among patients without COPD. The odds ratio for MCI was 1.60 in patients who had had COPD for five years or fewer and 2.10 in patients who had had COPD for more than five years.

—Erik Greb and Colby Stong

SAN FRANCISCO—Results of a single-center study suggest that a 3-drug regimen may be a safe and effective treatment option for patients with newly diagnosed or relapsed/refractory extranodal natural killer/T-cell lymphoma (ENKTL).

The combination of pegaspargase, gemcitabine, and oxaliplatin (P-Gemox) elicited a high rate of response in this cohort of 60 Chinese patients.

P-Gemox also produced higher survival rates than those previously observed with the EPOCH regimen.

Grade 1/2 myelosuppression occurred in more than half of patients in this study, and nearly three-quarters of patients experienced grade 1/2 nausea. But grade 3/4 adverse events were minimal.

Hui-qiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented these results at the 6th Annual T-cell Lymphoma Forum.

Dr Huang noted that advanced ENKTL is relatively resistant to anthracycline-based chemotherapy. And although the SMILE and AspaMetDex regimens are effective, they confer relatively severe toxicities and are inconvenient to administer.

“So chemotherapeutic combinations with high efficacy and low toxicities are urgently needed,” he said.

With this in mind, he and his colleagues assessed P-Gemox in 61 patients with ENKTL. Thirty-six patients were newly diagnosed, and 25 had relapsed/refractory disease. Roughly 69% of patients were male, and about 86% were older than 60 years of age.

Overall, 36.1% of patients had stage IE disease, 31.1% had stage IIE, 4.9% had stage IIIE, and 27.9% had stage IVE.

The relapsed/refractory patients had received a range of prior treatment regimens, including CHOP/L-ASP+CHOP, EPOCH, V-EPOCH, ICE, IMVP-16, and SMILE. And 13 patients had received radiotherapy.

For this study, all 61 patients received intravenous gemcitabine at 1000 mg/m² on days 1 and 8, intravenous oxaliplatin at 130 mg/m² on day 1, and intramuscular pegaspargase at 2500 U/m² on day 1. This regimen was repeated every 3 weeks.

Patients with stage IE/IIE disease received 3 cycles followed by radiotherapy (50-56 Gy). Relapsed/refractory patients received 2 to 6 cycles, and those who responded well were recommended for autologous transplant.

Response and subsequent treatment

Sixty patients were evaluable for response. (One patient in the newly diagnosed group was not evaluable).

The overall response rate (ORR) was 90%, with 63.3% of patients achieving a complete response (CR), 26.7% achieving a partial response (PR), and 8.3% maintaining stable disease (SD).

Among newly diagnosed patients, the ORR was 94.3%. CRs occurred in 74.3% of patients, PRs in in 20%, and SD in 5.7%.

And among the relapsed/refractory patients, the ORR was 84%. CRs were seen in 48% of patients, PRs in 36%, and SD in 12%.

“For patients with early stage disease, we found P-Gemox can further improve the outcomes of radiotherapy,” Dr Huang noted.

The treatment also provided a good bridge to transplant. Eight patients underwent transplant after achieving CR. One of these patients died 9 months after the procedure, but the other 7 patients were still in CR at a median of 14.6 months (range, 4.8-19.7 months).

‘Encouraging’ survival

The median follow-up was 29.5 months. The researchers confirmed progressive disease in 18 of the 61 patients—7 in the newly diagnosed group and 11 in the relapsed/refractory group.

Nine patients died of disease progression—1 in the newly diagnosed group and 8 in the relapsed/refractory group.

The 2-year overall survival was 86%, and the 2-year progression-free survival was 75.6%. Both overall and progression-free survival were superior in the newly diagnosed patients (P=0.054 and P=0.004, respectively).

“For the relapsed/refractory cases, considering they had already received a lot of previous treatments, we thought this outcome with P-Gemox is still quite encouraging,” Dr Huang said.

When the researchers compared overall survival with P-Gemox to previous results observed with EPOCH in newly diagnosed ENKTL patients (Huang et al, Leuk & Lymph 2011), they found P-Gemox was superior.

‘Tolerable’ toxicity

Toxicity with P-Gemox was tolerable and manageable, according to Dr Huang. The main adverse events were nausea and myelosuppression. But the rate of grade 3/4 events was low, and there were no treatment-related deaths.

Specifically, the grade 1/2 adverse events included nausea (73.8%), neutropenia (58%), thrombocytopenia (52.4%), hypoprotinemia (52.4%), anemia (52.4%), vomiting (49.2%), prolonged APTT (44.2%), elevated transaminase (34.1%), elevated bilirubin (27.9%), mucositis (24.5%), decreased fibrinogen (23%), elevated BUN (4.9%), intracranial bleeding (1.6%), stomach bleeding (1.6%), pancreatitis (1.6%), and herpes (1.6%).

Grade 3/4 adverse events included neutropenia (19.7%), thrombocytopenia (16.4%), hypoprotinemia (1.6%), anemia (1.6%), vomiting (3.2%), elevated transaminase (1.6%), and decreased fibrinogen (1.6%).

“We found that P-Gemox is an effective, safe, and convenient regimen in Chinese patients with ENKTL, both treatment-naïve and relapsed/refractory,” Dr Huang concluded. “These results provide a basis for subsequent studies.”

Dr Huang and his colleagues also presented the results of this research at the ASH Annual Meeting in December as abstract 642. (Information presented at the T-cell Lymphoma Forum differs from that in the ASH abstract).

SAN FRANCISCO—Results of a single-center study suggest that a 3-drug regimen may be a safe and effective treatment option for patients with newly diagnosed or relapsed/refractory extranodal natural killer/T-cell lymphoma (ENKTL).

The combination of pegaspargase, gemcitabine, and oxaliplatin (P-Gemox) elicited a high rate of response in this cohort of 60 Chinese patients.

P-Gemox also produced higher survival rates than those previously observed with the EPOCH regimen.

Grade 1/2 myelosuppression occurred in more than half of patients in this study, and nearly three-quarters of patients experienced grade 1/2 nausea. But grade 3/4 adverse events were minimal.

Hui-qiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented these results at the 6th Annual T-cell Lymphoma Forum.

Dr Huang noted that advanced ENKTL is relatively resistant to anthracycline-based chemotherapy. And although the SMILE and AspaMetDex regimens are effective, they confer relatively severe toxicities and are inconvenient to administer.

“So chemotherapeutic combinations with high efficacy and low toxicities are urgently needed,” he said.

With this in mind, he and his colleagues assessed P-Gemox in 61 patients with ENKTL. Thirty-six patients were newly diagnosed, and 25 had relapsed/refractory disease. Roughly 69% of patients were male, and about 86% were older than 60 years of age.

Overall, 36.1% of patients had stage IE disease, 31.1% had stage IIE, 4.9% had stage IIIE, and 27.9% had stage IVE.

The relapsed/refractory patients had received a range of prior treatment regimens, including CHOP/L-ASP+CHOP, EPOCH, V-EPOCH, ICE, IMVP-16, and SMILE. And 13 patients had received radiotherapy.

For this study, all 61 patients received intravenous gemcitabine at 1000 mg/m² on days 1 and 8, intravenous oxaliplatin at 130 mg/m² on day 1, and intramuscular pegaspargase at 2500 U/m² on day 1. This regimen was repeated every 3 weeks.

Patients with stage IE/IIE disease received 3 cycles followed by radiotherapy (50-56 Gy). Relapsed/refractory patients received 2 to 6 cycles, and those who responded well were recommended for autologous transplant.

Response and subsequent treatment

Sixty patients were evaluable for response. (One patient in the newly diagnosed group was not evaluable).

The overall response rate (ORR) was 90%, with 63.3% of patients achieving a complete response (CR), 26.7% achieving a partial response (PR), and 8.3% maintaining stable disease (SD).

Among newly diagnosed patients, the ORR was 94.3%. CRs occurred in 74.3% of patients, PRs in in 20%, and SD in 5.7%.

And among the relapsed/refractory patients, the ORR was 84%. CRs were seen in 48% of patients, PRs in 36%, and SD in 12%.

“For patients with early stage disease, we found P-Gemox can further improve the outcomes of radiotherapy,” Dr Huang noted.

The treatment also provided a good bridge to transplant. Eight patients underwent transplant after achieving CR. One of these patients died 9 months after the procedure, but the other 7 patients were still in CR at a median of 14.6 months (range, 4.8-19.7 months).

‘Encouraging’ survival

The median follow-up was 29.5 months. The researchers confirmed progressive disease in 18 of the 61 patients—7 in the newly diagnosed group and 11 in the relapsed/refractory group.

Nine patients died of disease progression—1 in the newly diagnosed group and 8 in the relapsed/refractory group.

The 2-year overall survival was 86%, and the 2-year progression-free survival was 75.6%. Both overall and progression-free survival were superior in the newly diagnosed patients (P=0.054 and P=0.004, respectively).

“For the relapsed/refractory cases, considering they had already received a lot of previous treatments, we thought this outcome with P-Gemox is still quite encouraging,” Dr Huang said.

When the researchers compared overall survival with P-Gemox to previous results observed with EPOCH in newly diagnosed ENKTL patients (Huang et al, Leuk & Lymph 2011), they found P-Gemox was superior.

‘Tolerable’ toxicity

Toxicity with P-Gemox was tolerable and manageable, according to Dr Huang. The main adverse events were nausea and myelosuppression. But the rate of grade 3/4 events was low, and there were no treatment-related deaths.

Specifically, the grade 1/2 adverse events included nausea (73.8%), neutropenia (58%), thrombocytopenia (52.4%), hypoprotinemia (52.4%), anemia (52.4%), vomiting (49.2%), prolonged APTT (44.2%), elevated transaminase (34.1%), elevated bilirubin (27.9%), mucositis (24.5%), decreased fibrinogen (23%), elevated BUN (4.9%), intracranial bleeding (1.6%), stomach bleeding (1.6%), pancreatitis (1.6%), and herpes (1.6%).

Grade 3/4 adverse events included neutropenia (19.7%), thrombocytopenia (16.4%), hypoprotinemia (1.6%), anemia (1.6%), vomiting (3.2%), elevated transaminase (1.6%), and decreased fibrinogen (1.6%).

“We found that P-Gemox is an effective, safe, and convenient regimen in Chinese patients with ENKTL, both treatment-naïve and relapsed/refractory,” Dr Huang concluded. “These results provide a basis for subsequent studies.”

Dr Huang and his colleagues also presented the results of this research at the ASH Annual Meeting in December as abstract 642. (Information presented at the T-cell Lymphoma Forum differs from that in the ASH abstract).

SAN FRANCISCO—Results of a single-center study suggest that a 3-drug regimen may be a safe and effective treatment option for patients with newly diagnosed or relapsed/refractory extranodal natural killer/T-cell lymphoma (ENKTL).

The combination of pegaspargase, gemcitabine, and oxaliplatin (P-Gemox) elicited a high rate of response in this cohort of 60 Chinese patients.

P-Gemox also produced higher survival rates than those previously observed with the EPOCH regimen.

Grade 1/2 myelosuppression occurred in more than half of patients in this study, and nearly three-quarters of patients experienced grade 1/2 nausea. But grade 3/4 adverse events were minimal.

Hui-qiang Huang, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, presented these results at the 6th Annual T-cell Lymphoma Forum.

Dr Huang noted that advanced ENKTL is relatively resistant to anthracycline-based chemotherapy. And although the SMILE and AspaMetDex regimens are effective, they confer relatively severe toxicities and are inconvenient to administer.

“So chemotherapeutic combinations with high efficacy and low toxicities are urgently needed,” he said.

With this in mind, he and his colleagues assessed P-Gemox in 61 patients with ENKTL. Thirty-six patients were newly diagnosed, and 25 had relapsed/refractory disease. Roughly 69% of patients were male, and about 86% were older than 60 years of age.

Overall, 36.1% of patients had stage IE disease, 31.1% had stage IIE, 4.9% had stage IIIE, and 27.9% had stage IVE.

The relapsed/refractory patients had received a range of prior treatment regimens, including CHOP/L-ASP+CHOP, EPOCH, V-EPOCH, ICE, IMVP-16, and SMILE. And 13 patients had received radiotherapy.

For this study, all 61 patients received intravenous gemcitabine at 1000 mg/m² on days 1 and 8, intravenous oxaliplatin at 130 mg/m² on day 1, and intramuscular pegaspargase at 2500 U/m² on day 1. This regimen was repeated every 3 weeks.

Patients with stage IE/IIE disease received 3 cycles followed by radiotherapy (50-56 Gy). Relapsed/refractory patients received 2 to 6 cycles, and those who responded well were recommended for autologous transplant.

Response and subsequent treatment

Sixty patients were evaluable for response. (One patient in the newly diagnosed group was not evaluable).

The overall response rate (ORR) was 90%, with 63.3% of patients achieving a complete response (CR), 26.7% achieving a partial response (PR), and 8.3% maintaining stable disease (SD).

Among newly diagnosed patients, the ORR was 94.3%. CRs occurred in 74.3% of patients, PRs in in 20%, and SD in 5.7%.

And among the relapsed/refractory patients, the ORR was 84%. CRs were seen in 48% of patients, PRs in 36%, and SD in 12%.

“For patients with early stage disease, we found P-Gemox can further improve the outcomes of radiotherapy,” Dr Huang noted.

The treatment also provided a good bridge to transplant. Eight patients underwent transplant after achieving CR. One of these patients died 9 months after the procedure, but the other 7 patients were still in CR at a median of 14.6 months (range, 4.8-19.7 months).

‘Encouraging’ survival

The median follow-up was 29.5 months. The researchers confirmed progressive disease in 18 of the 61 patients—7 in the newly diagnosed group and 11 in the relapsed/refractory group.

Nine patients died of disease progression—1 in the newly diagnosed group and 8 in the relapsed/refractory group.

The 2-year overall survival was 86%, and the 2-year progression-free survival was 75.6%. Both overall and progression-free survival were superior in the newly diagnosed patients (P=0.054 and P=0.004, respectively).

“For the relapsed/refractory cases, considering they had already received a lot of previous treatments, we thought this outcome with P-Gemox is still quite encouraging,” Dr Huang said.

When the researchers compared overall survival with P-Gemox to previous results observed with EPOCH in newly diagnosed ENKTL patients (Huang et al, Leuk & Lymph 2011), they found P-Gemox was superior.

‘Tolerable’ toxicity

Toxicity with P-Gemox was tolerable and manageable, according to Dr Huang. The main adverse events were nausea and myelosuppression. But the rate of grade 3/4 events was low, and there were no treatment-related deaths.

Specifically, the grade 1/2 adverse events included nausea (73.8%), neutropenia (58%), thrombocytopenia (52.4%), hypoprotinemia (52.4%), anemia (52.4%), vomiting (49.2%), prolonged APTT (44.2%), elevated transaminase (34.1%), elevated bilirubin (27.9%), mucositis (24.5%), decreased fibrinogen (23%), elevated BUN (4.9%), intracranial bleeding (1.6%), stomach bleeding (1.6%), pancreatitis (1.6%), and herpes (1.6%).

Grade 3/4 adverse events included neutropenia (19.7%), thrombocytopenia (16.4%), hypoprotinemia (1.6%), anemia (1.6%), vomiting (3.2%), elevated transaminase (1.6%), and decreased fibrinogen (1.6%).

“We found that P-Gemox is an effective, safe, and convenient regimen in Chinese patients with ENKTL, both treatment-naïve and relapsed/refractory,” Dr Huang concluded. “These results provide a basis for subsequent studies.”

Dr Huang and his colleagues also presented the results of this research at the ASH Annual Meeting in December as abstract 642. (Information presented at the T-cell Lymphoma Forum differs from that in the ASH abstract).

Cynomolgus monkey

Credit: Yuyu Niu et al.

Although monkeys can be useful as models of human disease, precisely modifying their genes has proven difficult.

Now, investigators say they’ve achieved precise gene modification in monkeys using the CRISPR/Cas9 system.

“Our study shows that the CRISPR/Cas9 system enables simultaneous disruption of 2 target genes in 1 step, without producing off-target mutations,” said Jiahao Sha, PhD, of Nanjing Medical University in Nanjing, China.

“Considering that many human diseases are caused by genetic abnormalities, targeted genetic modification in monkeys is invaluable for the generation of human disease models.”

Dr Sha and his colleagues described this research in Cell.

The CRISPR/Cas9 system is a gene-editing tool capable of targeting specific DNA sequences in the genome. Cas9 proteins, which are directed by single-guide RNAs to specific sites in the genome, generate mutations by introducing double-stranded DNA breaks.

Until now, the CRISPR/Cas9 system and other targeted gene-editing techniques were successfully applied to mammals such as mice and rats, but not to primates.

Dr Sha and his colleagues injected messenger RNA encoding Cas9, as well as single-guide RNAs designed to target 3 specific genes, into one-cell-stage embryos of cynomolgus monkeys.

After sequencing DNA from 15 embryos, the team found that 8 of these embryos showed evidence of simultaneous mutations in 2 of the target genes.

The researchers then transferred genetically modified embryos into surrogate females, one of which gave birth to a set of twins. By sequencing the twins’ DNA, the team found mutations in 2 of the target genes.

Moreover, the CRISPR/Cas9 system did not produce mutations at genomic sites that were not targeted. And this suggests the tool will not cause undesirable effects when applied to monkeys.

“With the precise genomic targeting of the CRISPR/Cas9 system, we expect that many disease models will be generated in monkeys,” said Weizhi Ji, PhD, of the Yunnan Key Laboratory of Primate Biomedical Research in Kunming, China.

“[This] will significantly advance the development of therapeutic strategies in biomedical research.”

Cynomolgus monkey

Credit: Yuyu Niu et al.

Although monkeys can be useful as models of human disease, precisely modifying their genes has proven difficult.

Now, investigators say they’ve achieved precise gene modification in monkeys using the CRISPR/Cas9 system.

“Our study shows that the CRISPR/Cas9 system enables simultaneous disruption of 2 target genes in 1 step, without producing off-target mutations,” said Jiahao Sha, PhD, of Nanjing Medical University in Nanjing, China.

“Considering that many human diseases are caused by genetic abnormalities, targeted genetic modification in monkeys is invaluable for the generation of human disease models.”

Dr Sha and his colleagues described this research in Cell.

The CRISPR/Cas9 system is a gene-editing tool capable of targeting specific DNA sequences in the genome. Cas9 proteins, which are directed by single-guide RNAs to specific sites in the genome, generate mutations by introducing double-stranded DNA breaks.

Until now, the CRISPR/Cas9 system and other targeted gene-editing techniques were successfully applied to mammals such as mice and rats, but not to primates.

Dr Sha and his colleagues injected messenger RNA encoding Cas9, as well as single-guide RNAs designed to target 3 specific genes, into one-cell-stage embryos of cynomolgus monkeys.

After sequencing DNA from 15 embryos, the team found that 8 of these embryos showed evidence of simultaneous mutations in 2 of the target genes.

The researchers then transferred genetically modified embryos into surrogate females, one of which gave birth to a set of twins. By sequencing the twins’ DNA, the team found mutations in 2 of the target genes.

Moreover, the CRISPR/Cas9 system did not produce mutations at genomic sites that were not targeted. And this suggests the tool will not cause undesirable effects when applied to monkeys.

“With the precise genomic targeting of the CRISPR/Cas9 system, we expect that many disease models will be generated in monkeys,” said Weizhi Ji, PhD, of the Yunnan Key Laboratory of Primate Biomedical Research in Kunming, China.

“[This] will significantly advance the development of therapeutic strategies in biomedical research.”

Cynomolgus monkey

Credit: Yuyu Niu et al.

Although monkeys can be useful as models of human disease, precisely modifying their genes has proven difficult.

Now, investigators say they’ve achieved precise gene modification in monkeys using the CRISPR/Cas9 system.

“Our study shows that the CRISPR/Cas9 system enables simultaneous disruption of 2 target genes in 1 step, without producing off-target mutations,” said Jiahao Sha, PhD, of Nanjing Medical University in Nanjing, China.

“Considering that many human diseases are caused by genetic abnormalities, targeted genetic modification in monkeys is invaluable for the generation of human disease models.”

Dr Sha and his colleagues described this research in Cell.

The CRISPR/Cas9 system is a gene-editing tool capable of targeting specific DNA sequences in the genome. Cas9 proteins, which are directed by single-guide RNAs to specific sites in the genome, generate mutations by introducing double-stranded DNA breaks.

Until now, the CRISPR/Cas9 system and other targeted gene-editing techniques were successfully applied to mammals such as mice and rats, but not to primates.

Dr Sha and his colleagues injected messenger RNA encoding Cas9, as well as single-guide RNAs designed to target 3 specific genes, into one-cell-stage embryos of cynomolgus monkeys.

After sequencing DNA from 15 embryos, the team found that 8 of these embryos showed evidence of simultaneous mutations in 2 of the target genes.

The researchers then transferred genetically modified embryos into surrogate females, one of which gave birth to a set of twins. By sequencing the twins’ DNA, the team found mutations in 2 of the target genes.

Moreover, the CRISPR/Cas9 system did not produce mutations at genomic sites that were not targeted. And this suggests the tool will not cause undesirable effects when applied to monkeys.

“With the precise genomic targeting of the CRISPR/Cas9 system, we expect that many disease models will be generated in monkeys,” said Weizhi Ji, PhD, of the Yunnan Key Laboratory of Primate Biomedical Research in Kunming, China.

“[This] will significantly advance the development of therapeutic strategies in biomedical research.”

Red blood cells

Credit: NHLBI

The apoptosis inhibitor aurin tricarboxylic acid (ATA) is active against paroxysmal nocturnal hemoglobinemia (PNH), according to research published in PLOS ONE.

PNH is a rare condition in which red blood cells (RBCs) become vulnerable to attacks by the complement immune system and subsequently rupture.

This can lead to complications such as anemia, kidney disease, and fatal thromboses.

PNH results from a lack of 2 proteins that protect RBCs from destruction: decay-accelerating factor (CD55), an inhibitor of alternative pathway C3 convertase, and protectin (CD59), an inhibitor of membrane attack complex (MAC) formation.

Because previous studies suggested that ATA selectively blocks complement activation at the C3 convertase stage and MAC formation at the C9 insertion stage, researchers thought ATA might prove effective against PNH.

First, they compared RBCs from 5 patients with PNH (who were on long-term treatment with eculizumab) to RBCs from healthy individuals.

Despite the eculizumab, the PNH patients’ RBCs were twice as vulnerable to complement-induced lysis as the healthy subjects’ RBCs. And western blot revealed both C3 and C5 convertases on the membranes of patients’ RBCs.

However, when the researchers added ATA to patients’ blood samples, the RBCs were protected from complement attack. In fact, the drug restored the RBCs’ resistance to the same level as normal RBCs.

“Our study suggests that ATA could offer more complete protection as an oral treatment for PNH, while eliminating the need for infusions,” said study author Patrick McGeer, MD, PhD, of the University of British Columbia in Vancouver, Canada.

“PNH is a disease that may happen to anyone through a chance mutation, and, if nature were to design a perfect fix for this mutation, it would be ATA.”

Dr McGeer added that many diseases are caused or worsened by an overactive complement immune system. So his group’s findings could have implications for conditions such as Alzheimer’s disease, Parkinson’s disease, macular degeneration, amyotrophic lateral sclerosis, multiple sclerosis, and rheumatoid arthritis.

He and his colleagues are now proceeding with further testing, and Dr McGeer expects ATA could be available in clinics within a year.

Red blood cells

Credit: NHLBI

The apoptosis inhibitor aurin tricarboxylic acid (ATA) is active against paroxysmal nocturnal hemoglobinemia (PNH), according to research published in PLOS ONE.

PNH is a rare condition in which red blood cells (RBCs) become vulnerable to attacks by the complement immune system and subsequently rupture.

This can lead to complications such as anemia, kidney disease, and fatal thromboses.

PNH results from a lack of 2 proteins that protect RBCs from destruction: decay-accelerating factor (CD55), an inhibitor of alternative pathway C3 convertase, and protectin (CD59), an inhibitor of membrane attack complex (MAC) formation.

Because previous studies suggested that ATA selectively blocks complement activation at the C3 convertase stage and MAC formation at the C9 insertion stage, researchers thought ATA might prove effective against PNH.

First, they compared RBCs from 5 patients with PNH (who were on long-term treatment with eculizumab) to RBCs from healthy individuals.

Despite the eculizumab, the PNH patients’ RBCs were twice as vulnerable to complement-induced lysis as the healthy subjects’ RBCs. And western blot revealed both C3 and C5 convertases on the membranes of patients’ RBCs.

However, when the researchers added ATA to patients’ blood samples, the RBCs were protected from complement attack. In fact, the drug restored the RBCs’ resistance to the same level as normal RBCs.

“Our study suggests that ATA could offer more complete protection as an oral treatment for PNH, while eliminating the need for infusions,” said study author Patrick McGeer, MD, PhD, of the University of British Columbia in Vancouver, Canada.

“PNH is a disease that may happen to anyone through a chance mutation, and, if nature were to design a perfect fix for this mutation, it would be ATA.”

Dr McGeer added that many diseases are caused or worsened by an overactive complement immune system. So his group’s findings could have implications for conditions such as Alzheimer’s disease, Parkinson’s disease, macular degeneration, amyotrophic lateral sclerosis, multiple sclerosis, and rheumatoid arthritis.

He and his colleagues are now proceeding with further testing, and Dr McGeer expects ATA could be available in clinics within a year.

Red blood cells

Credit: NHLBI

The apoptosis inhibitor aurin tricarboxylic acid (ATA) is active against paroxysmal nocturnal hemoglobinemia (PNH), according to research published in PLOS ONE.

PNH is a rare condition in which red blood cells (RBCs) become vulnerable to attacks by the complement immune system and subsequently rupture.

This can lead to complications such as anemia, kidney disease, and fatal thromboses.

PNH results from a lack of 2 proteins that protect RBCs from destruction: decay-accelerating factor (CD55), an inhibitor of alternative pathway C3 convertase, and protectin (CD59), an inhibitor of membrane attack complex (MAC) formation.

Because previous studies suggested that ATA selectively blocks complement activation at the C3 convertase stage and MAC formation at the C9 insertion stage, researchers thought ATA might prove effective against PNH.

First, they compared RBCs from 5 patients with PNH (who were on long-term treatment with eculizumab) to RBCs from healthy individuals.

Despite the eculizumab, the PNH patients’ RBCs were twice as vulnerable to complement-induced lysis as the healthy subjects’ RBCs. And western blot revealed both C3 and C5 convertases on the membranes of patients’ RBCs.

However, when the researchers added ATA to patients’ blood samples, the RBCs were protected from complement attack. In fact, the drug restored the RBCs’ resistance to the same level as normal RBCs.

“Our study suggests that ATA could offer more complete protection as an oral treatment for PNH, while eliminating the need for infusions,” said study author Patrick McGeer, MD, PhD, of the University of British Columbia in Vancouver, Canada.

“PNH is a disease that may happen to anyone through a chance mutation, and, if nature were to design a perfect fix for this mutation, it would be ATA.”

Dr McGeer added that many diseases are caused or worsened by an overactive complement immune system. So his group’s findings could have implications for conditions such as Alzheimer’s disease, Parkinson’s disease, macular degeneration, amyotrophic lateral sclerosis, multiple sclerosis, and rheumatoid arthritis.

He and his colleagues are now proceeding with further testing, and Dr McGeer expects ATA could be available in clinics within a year.