Safety overview of new disease-modifying antirheumatic drugs

Rheum Dis Clin N Am 30 (2004) 237 – 255

Safety overview of new disease-modifying antirheumatic drugs John J. Cush, MD Presbyterian Hospital of Dallas, 8200 Walnut Hill Lane, Dallas, TX 75231, USA

Beginning in 1998, a surge of new agents has expanded treatment options for rheumatoid arthritis (RA) patients. Although the disease-modifying potential of these agents is encouraging, their use must be weighed against an evolving array of new safety concerns. Use of these novel compounds is often restricted by cost and safety concerns and is usually limited to more advanced or refractory clinical trial patients [1]. Although clinical trials have shown us the most common adverse events associated with their use, the true safety profile of these drugs requires the expanded use in the postmarketing era among a representative RA population outside of the constraints of clinical trials. Because of the popularity of these agents with patients and rheumatologists alike, clinicians must be prepared to discuss the potential risks associated with novel disease-modifying antirheumatic drugs (DMARDs) and biologic therapies as they begin to appear with greater frequency in practice. This article discusses the safety issues arising from clinical trial and postmarketing experience with several new and commonly used agents, with specific emphasis on adalimumab, etanercept, infliximab, anakinra, and leflunomide [2 –6]. Historically, the objective of RA therapy has been to improve pain, avoid articular (radiographic) damage, and preserve function. Although logical, these goals were not always achievable. It was discovered in the 1980s that available therapies were seldom capable of true disease modification. Nearly 20 years ago, Dr. Verner Wright prophetically stated that ‘‘all too frequently physicians write ‘doing well’ repeatedly in the chart of a patient who has become progressively disabled before their eyes’’ [7]. A new era was born out of the realization that: (1) joint damage begins early and is progressive over time; (2) individual DMARD potency and durability was disappointing; and (3) many DMARD failures can be linked to drug toxicity. The introduction of methotrexate (MTX) heralded this new era of improved outcomes. MTX was ultimately shown to be more effective,

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more durable, and truly disease modifying (eg, better radiographic outcomes and mortality rates [8]) when compared with other DMARDs. MTX has become the gold standard against which all new therapies will be judged. Since then research has yielded newer and equally if not more potent DMARDs that now afford many patients a real chance of remission. Hence our current and future goals for RA therapy have been redirected at remission, complete suppression of immunedriven inflammation, avoidance of tissue damage or untoward treatment side effects, and, ultimately, disease prevention. This admittedly aggressive paradigm shift is only possible if these novel therapies deliver on their promise of superior efficacy and safety.

A new era of novel drug therapy Optimal and safe use of any drug should be based on proper use, including appropriate dosing and patient selection. Since 1998 five new DMARD/biologic therapies have been approved by the US Food and Drug Administration (FDA) for use in RA: leflunomide, infliximab, etanercept, adalimumab, and anakinra. The FDA has established indications for the use of these agents based on clinical trial data; in general, all of them are approved for use in RA patients who have not shown an adequate response to a reasonable dose and duration of MTX or other traditional DMARDs. These agents have been approved as monotherapy or for use in combination with MTX. MTX serves as a background therapy when either infliximab or adalimumab are prescribed, because these monoclonal antibodies may be immunogenic, and MTX has been shown to reduce the immunogenicity of both. It has been shown that the background use of MTX will lessen human antichimeric antibodies or human antihuman antibodies that may affect the efficacy or toxicity [3,5]. All have been approved for the control of signs and symptoms of RA. However, only leflunomide, infliximab, etanercept, and adalimumab have been shown to retard radiographic damage in RA. Infliximab and leflunomide had been shown to improve quality of life outcomes in 2-year studies. To date, only etanercept has been indicated for use in early or DMARD naı¨ve RA patients [9], although the published results of early RA trials with infliximab and adalimumab are forthcoming. In addition, only etanercept is approved for use in juvenile arthritis. The American College of Rheumatology has established treatment guidelines for RA. Tumor necrosis factor (TNF) inhibitors are one of several options to be considered after an inadequate response to maximally tolerated doses of MTX [10]. Wolfe and colleagues [11] have declared the elimination of synovitis and disease activity as the primary goal of RA treatment. Their consensus guidelines suggest that RA patients should receive the best DMARD available and as early as possible. Moreover, DMARDs, combination DMARDs, and biologic therapies should be administered early based on risk factors that have been shown to correlate with poorer outcomes, such as aggressive disease. Hence aggressive therapy should be given to those with aggressive disease and should not be reserved for

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those with long-standing, end-stage, or DMARD-resistant disease. Lipsky and colleagues [12] have defined aggressive RA as a patient with any combination of the following: many swollen joints, functional disability, high levels of acute phase reactants or rheumatoid factor levels, and the presence of nodules, radiographic erosions, or extra-articular manifestations. The pharmacokinetic differences between these agents may influence drug selection. Patients may be offered a daily pill (leflunomide) or subcutaneous daily (anakinra) or twice weekly (etanercept), or every other week (adalimumab) injections or an infusion delivered once every 2 months (infliximab). Patients often clearly prefer one of the above, often driven by convenience, compliance, employment, lifestyle, familiarity with subcutaneous injections, or venous access issues. For many clinicians, choosing a DMARD is often based on familiarity, patient request or disease severity or safety concerns. Treatment decisions must weigh the need and potential for clinical improvement against the concern over drug-associated risks. The balance between these concerns, as it impacts the choice of therapy, will be influenced by physician and patient attitudes. Patients should be encouraged to voice their treatment priorities. Ultimately the decision to use conventional or newer therapies should be jointly considered by the patient and physician who can weigh the patient’s quality of life, potential drug efficacy, and reasonable toxicity expectations. At the time of drug initiation, patients should receive written and verbal instruction with regard to the use and common toxicities associated with these parenterally administered therapies. Written materials, video instruction, and teaching kits have been developed by the manufacturers and can be used to instruct and ease patient concerns. Moreover, these materials also have toll-free telephone numbers to assist patients with proper drug use or specific problems.

Leflunomide safety Leflunomide was studied in more than 2000 RA patients and since its approval in 1998 has been given to nearly 400,000 patients worldwide. Leflunomide is an antiproliferative isoxazole compound that was developed for use in RA. Leflunomide inhibits dihydroorotate dehydrogenase and subsequent pyrimidine synthesis. Leflunomide is well absorbed in the gastrointestinal tract and is metabolized to its M1 metabolite, which is responsible for most of the drug’s biologic effects in vivo [6]. The half-life of M1 is long, ranging from 15 to 18 days. The M1 compound is extensively bound to albumin and free fraction is nearly doubled in RA and patients with renal failure (although no dose adjustments need be made). The drug is probably metabolized in the gastrointestinal tract and liver and excreted equally in the feces and urine. The drug can be removed from enterohepatic recirculation by using activated charcoal or cholestyramine. Patients who require treatment of an adverse event can receive 8 g of cholestyramine three times a day for 2 days, which will result in a 65% reduction in plasma drug levels. For

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pregnancy issues (male or female) or serious toxicity concerns, a complete drug washout can be accomplished using 8 g of cholestyramine three times a day for 11 days to drop drug levels below 0.2 mg/L. Without the elimination procedure, it may take 2 years to achieve M1 metabolite levels less than 0.02 mg/L. Several clinical trials performed in RA have shown that leflunomide is clearly superior to placebo and is at least equal in efficacy to MTX [6,13,14]. The combination of leflunomide and MTX has been shown to be effective when given to MTX partial responders [9]. Common toxicities observed in clinical trials included diarrhea (17%), nausea (9%), abdominal pain (5%), hypertension 10% (new onset 2%), alopecia (10%), rash (10%), headache (7%), increased hepatic enzymes (5% –10%), and paraesthesias (2%). It is recommended that patients have blood counts and hepatic enzymes monitored monthly for the first 6 months and then every 6 to 8 weeks thereafter. Following the release of leflunomide in 1998, postmarketing reports of new and uncommon toxicities began to appear, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Moreover, reports of bone marrow suppression manifest as pancytopenia, agranulocytosis, thromobcytopenia have also been reported in patients taking leflunomide alone or in combination with other immunosuppressives such as MTX. Several of these patients had a prior history of cytopenias, suggesting this may be a risk factor as well. In such patients, prompt discontinuation and initiation of a drug washout is recommended. Hepatotoxicity In clinical trials, elevations of hepatic enzymes were seen in 18% to 28% of patients (Table 1). However, extreme elevations (>3 times normal limits) were seen in 1.5% to 4.4% of patients, and these were seldom classified as serious adverse events (2.2% –3.8%) or lead to drug withdrawal (1.5% –7.1%). When leflunomide was combined with MTX use in a clinical trial [6,9], a similar incidence of either aspartate aminotransferase or alanine aminotransferase elevation was seen (23% – 28%), and higher level elevations (>3 times normal limits) were only seen in 1.5% to 3.8% of patients. Most of these extreme elevations returned to normal with observation alone. However, persistent elevations of hepatic enzymes Table 1 Frequency of hepatic enzyme elevations on leflunomide in three clinical trials

ALT >1.2 ULN AST >2.0 ULN Withdrawal for LFTs ALT > 3.0 ULN Serious adverse event due to LFTs

US301

MN301

MN302

28.6 11.0 7.1 4.4 2.2

18.8 2.3 1.5 1.5 3.8

21.4 7.0 1.6 2.6 3.8

Data are expressed as percentages. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; LFTs, liver function tests; ULN, upper limit of normal. Data from Leflunomide package insert.

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should not be tolerated and should lead to dose adjustments, discontinuation, or a drug washout as required. In the first 104,000 patient years of leflunomide use, there were 296 reports of liver toxicity detailed by the European Agency for the Evaluation of Medicinal Products [15]. These reports were reviewed by the FDA and other agencies. Most of these (232) were sporadic hepatic enzyme (liver function test) elevations, many of which occurred in patients receiving other known hepatotoxins (eg, nonsteroidal anti-inflammatory drugs, MTX, and so forth), and 65 of these were classified as ‘‘serious.’’ Celecoxib and diclofenac were the most commonly identified hepatotoxins also taken by these patients. These agents and leflunomide are both metabolized by the same cytochrome P450 2C9 pathway, suggesting a mechanism for additive toxicity. There were 15 reports of liver failure, 2 reports of cirrhosis, and 15 deaths. One third of these deaths were hepatic (including diagnoses of liver failure, hepatic necrosis, hepatitis, and cholestatic jaundice); the other two thirds were due to nonhepatic causes (sepsis, multiorgan failure, interstitial lung disease, gastrointestinal bleeding, pulmonary embolism, StevensJohnson syndrome, pancreatitis). Following recommended prescribing guidelines and laboratory monitoring would have avoided many of these adverse events. A ‘‘Dear Doctor’’ letter and other literature have recommended strict adherence to prescribing guidelines, regular blood monitoring, and caution when using leflunomide in conjunction with other hepatotoxins. Leflunomide should not be used in:      

patients known to have hypersensitivity to leflunomide; patients who have persistent liver dysfunction; patients who have hepatitis C or B; known alcohol abusers; patients who are pregnant or who are planning a pregnancy; or patients who have an active infection.

The issue of serious hepatotoxicity was again recently reviewed by the FDA in 2003 [16]. After reviewing several large RA patient databases and managed care cohorts, it was estimated that the risk of hospitalization for leflunomide-related hepatitis was approximately 1 in 5000 (0.02%) and that no cases of hepatocellular necrosis with jaundice (ie, liver failure) were seen in over 13,700 patients. Nonetheless, the Medwatch Adverse Event Reporting System has identified few reports of acute liver failure related to leflunomide use and has reported that population-based cohort analyses confirm this association to be rare. Pregnancy risk Leflunomide is a known teratogen and should not be used in women who are pregnant or plan to be in the near future. Women and men who are taking leflunomide and are of child-bearing potential should be cautioned about the need for reliable contraception.

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Safety of cytokine inhibitors Before FDA approval, a large number of RA patients were studied in controlled clinical trials of etanercept (1272 patients), infliximab (1372 patients), adalimumab (2468 patients), and anakinra (2932 patients) [2 –5,17]. While common adverse events were defined during the conduct of phase II to III clinical trials, the full scope of potential toxicities has evolved in the postmarketing era, with up to 5 years and nearly 600,000 patients treated with cytokine inhibitors thus far [18]. Injection site reactions The most common side effect seen in clinical trials of self-administered biologics is that of infection site reactions (ISRs), ranging from 18.5% to 71% (Table 2) for adalimumab and anakinra, respectively. These rates appear to be significantly greater than that seen in clinical practice; the reasons for this are unclear. The results of the recently reported TEMPO trial of monotherapy with either MTX or etanercept versus a combination of the two has shown a 50% reduction in ISRs in patients who received the combination (unpublished data). Nonetheless, drug discontinuation due to ISRs was uncommon (0.3%– 7%) [2 –5,17]. ISRs are mild to moderate in severity, are primarily seen in the first few weeks of agent use, become less prominent over time, and are uncommon after 2 months of agent use [19]. Patients may complain of local erythema, dysesthesia (with injection), ecchymoses, urticaria, or pruritis. ISRs involving etanercept or adalimumab usually last 3 to 5 days, and those involving anakinra may last 7 to 10 days. Uncommon ISRs include recall reactions (redness at one or several prior injection sites when subsequent injections are given), recurrent/ chronic ISRs (which may be painful), large plaquelike ISRs, or subcutaneous atrophy at injection sites (unpublished observations). Patients with ISRs generally require no therapy, although analgesics, antipruritics, or topical corticosteroid creams may be used to control symptoms. Patients receiving injectable biologics should be forewarned of the potential for ISRs and should be instructed to rotate injection sites on the anterior thighs or abdomen.

Table 2 Administration reactions with anticytokine drugs

Injection site reactions Anakinra Etanercept Adalimumab Infusion reactions Infliximab

Frequency

Discontinuation

71 37 18.5

7 <2 0.3

22

1.9

Data are expressed as percentages. Data from Cush JJ. Cytokine therapies. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman, editors. Rheumatology. 3rd edition. Edinburg: Mosby; 2003. p. 461 – 84.

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Infusion reactions Intravenous infusion time for infliximab is usually 2 to 3 hours, and most patients experience no untoward effects during or after the infusion. Nonetheless, infusion-related reactions are unpredictable and may occur in patients taking prednisone or MTX. It is presumed these events may be less common in patients who also receive MTX due to reduced human antichimeric antibody formation. Mild to moderate infusion reactions may occur in up to 20% of patients—usually during the infusion or within 1 to 2 hours after—and rarely require cessation of therapy [20]. Common manifestations include urticaria, pruritus, rash, headache, flushing, fever, chills, nausea, tachycardia, or dyspnea. In many instances, infusion reactions occur when the infusion is administered too quickly (ie, in less than 2 hours). Hence many can be treated by slowing the rate of infusion and treating symptomatically. Premedication is usually not given, but some patients can be premedicated with either acetaminophen, nonsedating antihistamines, or short-acting corticosteroids to prevent such reactions should these nuisances become problematic. Severe infusion reactions occur in 2% to 3% of patients and may lead to discontinuation of therapy [19,20]. Symptoms of chest tightness, bronchospasm, hypotension, diaphoresis, anaphylaxis, or ‘‘feelings of impending doom’’ should prompt the clinician to assess or intervene. In such instances, therapy should be stopped and supportive or emergent care should be administered until the patient is stabilized. For these reasons infliximab infusions should be performed with trained medical personnel in attendance with access to parenteral corticosteroids, diphenhydramine, and epinephrine. It is not felt that these manifestations represent an acute hypersenstitivity reaction as tryptase levels and immunoglobulin E have been normal when studied [21]. Some patients have been rechallenged with infliximab or undergone a desensitization protocol while being monitored in an intensive care facility, but this should only be done by physicians who are experienced with the use of this agent [22]. Uncommon reports of delayed infusion reactions (occurring 2 to 12 days after infusion) have been seen in Crohn’s patients who have long treatment-free intervals [5]. Clinical findings included myalgia, arthralgia, fever, rash, urticaria, swelling of hands or lips, dysphagia, and headache. Other rarely encountered cutaneous toxicities ascribed to TNF inhibition include lupuslike rashes (see below), hypersensitivity vasculitis, folliculitis, pernio, granuloma annulare, and lichenoid eruptions [23,24]. Infection Because TNF and interleukin (IL)-1 are important regulators of host responses to microbial challenge, infection continues to be a primary concern when using cytokine inhibitors. Data from randomized, controlled clinical trials show nearly one third of RA patients on a cytokine inhibitor experienced a minor infection. These included reports of upper respiratory tract infections, bronchitis, sinusitis, pharyngitis, and urinary tract infections. Although common, these infections were

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generally noted at the same rate in placebo-treated RA patients. Moreover, these patients were treated symptomatically and were not exited from the trials, and no serious outcomes were observed. Hence, there is little evidence from clinical trials to support the practice of delay or discontinuation of TNF inhibitor therapy when an upper respiratory tract infection or other minor infection occurs. Current prescribing guidelines suggest that patients should be monitored for signs and symptoms of infection when taking either a TNF or IL-1 inhibitor and that these agents should not be used in patients with active, serious infections or chronic recurrent infections. There are no guidelines addressing TNF inhibitor use in perioperative patients who undergo elective surgery. Serious or life-threatening infectious events were uncommonly seen in clinical trials and were further defined in postmarketing analyses. Serious infections Because the inflammatory response is crucial to the control of certain infections, the possibility that TNF inhibition may place patients at a greater risk of infection has been examined [25 –32]. RA patients exhibit a six- to ninefold increase in infection-related deaths. Risk factors for serious infectious events (SIEs) in RA include the severity of disease, use of corticosteroids, comorbidities, skin breakdown (eg, open cutaneous ulcers or incisions) or joint surgery [17]. SIEs are defined as serious adverse events of an infectious etiology (eg, sepsis, pneumonia, cellulitis, bone or joint infections) that require hospitalization or pose significant morbid or mortal risk. During controlled clinical trials, SIEs were rarely reported but were not observed to be greater than that observed in placebotreated controls. Thus serious infections occurred in 6.1% of infliximab and 8.1% of placebo patients in the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (the ATTRACT trial) [33]. In a 1-year early RA trial in which patients received 25 mg of MTX and 25 mg of etanercept BIW, 3.7% of MTX patients and 1.9% of etanercept patients exhibited serious infections [34]. The serious infection rate for adalimumab was 0.04 infections per year, compared with 0.02 per year in placebo-treated patients [32]. SIEs occurred in 1.8% of anakinratreated patients compared with 0.7% for those taking placebos. Pneumonia was the most common SIE noted in the anakinra trials; the risk of SIEs was higher in patients on corticosteroids (3%) and patients with a history of asthma (5.5%) [35]. The risk of serious infection following the use of TNF inhibition was first questioned after the release of etanercept [25]. During controlled clinical trials, the number of serious infections was similar between RA patients who received placebo (1.3%) and etanercept (0.9%). However, following FDA approval, 30 serious infections were reported among the first 25,000 patients receiving etanercept, six of whom died. A 0.12% SIE rate was observed in the postmarketing experience, but this was still far lower than that seen in all etanercept-treated patients in clinical trials. Risk of infectious death was greatest in the first 16 weeks after drug initiation and may have been enhanced by the presence of pre-existing infections (chronic or recurrent cutaneous ulcers), long-standing RA, extra-

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articular manifestations, prednisone therapy, or comorbidities (congestive heart failure, diabetes mellitus, or renal insufficiency). It should be noted that postmarketing surveillance data may be limited by significant underreporting. Historically, serious infections in RA have been reported to occur at a rate of 0.03 to 0.9 SIEs per patient year of drug exposure [17,27 –29]. During the clinical trial development of etanercept, infliximab, and adalimumab, the observed serious infection rate was 0.03 to 0.04 SIEs per patient year and was equal to rates seen in placebo controls [3– 5,36]. Postmarketing surveillance has shown the rates of SIEs with etanercept and infliximab to be 0.007 SIEs per patient year. It should be noted there is significant underreporting with postmarketing surveillance; thus these rates may be 10 to 100 times more common in the RA population. Although there continues to be reports of SIEs in RA patients [36], the rarity of these events, using current prescribing guidelines, suggests that TNF inhibitors have little if any contribution to the risk of infection in most RA patients. Current package labeling for all TNF inhibitors has been updated to state that patients developing a new infections should be monitored closely; that TNF inhibitors should be discontinued in the case of serious infections or sepsis; and that these drugs should be avoided in patients who have active infections, including chronic or localized infections. Physicians should exercise caution if considering a cytokine inhibitor in patients with a history of recurrent infections or a comorbid conditions known to predispose to infection (heart failure, diabetes mellitus, renal insufficiency, and so forth). Clinicians should also consider whether or not corticosteroid use or patient debility will influence the risk-versusbenefit expectations associated with TNF blocker use. Although these therapies may be indicated as inflammation and severity increases, there may come a point at which their use posses increased toxicity risk with little or uncertain chance of benefit. Moreover, the presence of other infectious risk factors may lower this threshold. In summary, the clinician must carefully select patients who receive TNF inhibitors, so as to limit their potential toxicity, including infectious risk. Lastly, it should be noted that the combined use of anakinra (an IL-1 inhibitor) and a TNF inhibitor (eg, etanercept, infliximab, and so forth) should be discouraged, because a higher rate of SIEs (7%) was seen with anakinra and etanercept combination therapy in both a 58-patient open-label trial [37] and in a much larger placebo-controlled trial (L. Moreland, personal communication). Moreover, the controlled trial failed to show any benefit with the use of combination anticytokine therapy. Tuberculosis and opportunistic infections Opportunistic infections with tuberculosis (TB) and other opportunistic or granulomatous infections were predicted with TNF inhibition based on animal studies showing the protective role of TNF (but not IL-1) against infections with Mycobacterium tuberculosis, Candida, Histoplasma, Listeria, Leshmania, and Malaria [17,38]. TNF plays a crucial role in granuloma formation, and stabilization thereby fosters containment and sequestration of these pathogens. Myco-

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bacterial infections have been been described in patients receiving infliximab, etanercept, and adalimumab but have not been associated with anakinra use. The risk of TB and opportunistic infections has been reviewed by the FDA [30 – 32]. As of August 2002, over 515,000 patients were receiving these agents. Most of this worldwide use occurred in the United States, with only 10% to 34% of etanercept and infliximab use occurring in Europe. However, the vast majority of the nearly 300 worldwide cases of TB have occurred in Europe and other countries outside the use, where TB is an endemic public health problem. By 2003, rising numbers of postmarketing tuberculosis cases were seen in patients receiving infliximab (277 patients) and etanercept (38 patients), and 13 tuberculosis cases arose during the adalimumab clinical trials [34,35]. Most of these TB infections occurred in the first 6 to 8 months of use, although a more variable latency period was observed with etanercept use (mean: 11 months). The chronology and strong association with endemic infections suggests reactivation of latent tubercle bacilli from TNF inhibition. Extrapulmonary presentation was seen in 30% to 50% of cases reported and included fever of unknown origin, miliary tuberculosis or tuberculosis-associated lymphadenopathy, peritonitis, meningitis, and vertebral and bladder disease. Because of this association, RA patients considering the use of a TNF inhibitor should undergo tuberculin skin testing according to the American Thoracic Society and Centers for Disease Control and Prevention guidelines [39]. These guidelines state that all high-risk populations (including immigrants from endemic countries, recent TB contacts, chronic prednisone users, intravenous drug users, persons infected with HIV, and transplant and immunosuppressed patients) should be screened and that greater than 5 mm of induraton should be considered a positive result [39 –41]. Although chronic prednisone use is a risk factor for serious or opportunistic infections, it is unproven that MTX or other DMARDs significantly influence the incidence of opportunistic infections in RA. Tuberculin skin testing is recommended for patients initiating infliximab or adalimumab. Although most rheumatologists will routinely do the same in RA patients receiving etanercept, this is not mandated by the FDA [3 –5]. Control antigens and chest radiographs are not routinely indicated [39,40]. Skin testing should be read within 48 to 72 hours by a health care provider. Those previously vaccinated with BCG should also be tested and treated appropriately if tuberculin skin tests positive [39,40]. The impact of screening was observed in the adalimumab clinical trials when before screening procedures a 1.5% TB infection rate was seen and after screening procedures were implemented this dropped to 0.26% TB infection rate for those on adalimumab [32]. Chest radiographs are indicated for patients who exhibit signs and symptoms of pulmonary infection, have had recent contact with infected individuals, or are immunosuppressed. Patients found to have a positive tuberculin skin test should be started on isoniazid therapy, and TNF inhibitor therapy can commence immediately. Those identified as having active infection should be started on appropriate multidrug therapy, and TNF inhibitor therapy should be withheld until control of active infection is certain (at least 3 – 4 months).

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Other opportunistic infections have also been seen with TNF inhibitors, including atypical mycobacteria, histoplasma, listeria, pneumocystis, coccidioides, listeria, aspergillous, Nocardia, Candida, sporotrichosis, and cytomegalovirus [17,42,43]. Because no reliable skin testing exists for these infections, clinicians must maintain a high-index suspicion for opportunistic infections in RA patients treated with TNF inhibitors and should closely monitor patients for suggestive symptoms and signs, especially in endemic areas. An aggressive approach to diagnosis and treatment of these infections is advised. Demyelinating disorders Multiple sclerosis (MS), optic neuritis, and other forms of demyelinating neurologic dysfunction have been described when using etanercept, infliximab, and adalimumab [3– 5,44 –47]. These reports include new-onset optic neuritis, de novo MS, recurrence or flare of MS, encephalitis, myelitis, Guillain-Barre´ syndrome, chronic inflammatory demyelinating polyneuropathy, neuropathy, transverse myelitis, seizures, and leukoencephalopathy while receiving either etanercept, infliximab, or adalimumab. Other than a prior history of MS or optic neuritis, no predictive factors have been identified. Nearly all of these cases improved or resolved with discontinuation of TNF inhibitor therapy. Given the rarity of these events, it is unknown if these low rates exceed that seen in general or rheumatoid populations. Support for a causative effect comes from clinical trials. Open-label infliximab use has been shown to worsen MRI changes in two active MS patients [45]. In a placebo-controlled trial, lenercept (soluble p55 TNF receptor IgE fusion protein) was given to 168 relapsing/remitting MS patients who had shown to increase the number of MS flares [46]. Thus, TNF inhibitors should be used cautiously or avoided in patients with MS or a history of MS, optic neuritis, or other demyelinating disorders. Anakinra has not been linked with these complications. Hematologic effects Pancytopenia and aplastic anemia have rarely been ascribed to etanercept or infliximab [17,44]. There have been 15 reported cases of pancytopenia with infliximab and 12 cases of pancytopenia and 4 aplastic anemia with etanercept. A minority of these resulted in death. Cytopenias developed in the first few weeks (median 4 weeks) after initiating TNF inhibitors. Reasons underlying the sporadic association between etanercept and aplastic anemia are unclear. These events could possibly be attributed to comorbidities or other myelosuppressive drugs in use. Periodic monitoring (every 3– 6 months) of blood cell counts should be considered. Patients with features of blood dyscrasias (fever, pallor, bleeding, sore throat) should be evaluated for this complication. Anakinra has occasionally been associated with a 10% to 20% drop in leukocyte counts in nearly 8% of patients [2]. Severe leukopenia was observed in 0.3% of patients, but aplastic anemia has not been reported.

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Heart failure TNF has been presumed to play a crucial role in the pathogenesis of heart failure and cardiac cachexia [17]. TNF has been shown to have negative inotropic effects on the myocardium and cause myocyte dysfunction; therefore, it was expected that TNF inhibition would improve cardiac outcomes. Instead, both etanercept and infliximab clinical trials in heart failure were suspended prematurely for lack of effect or poorer outcomes [31,48,49]. Etanercept has been tested in two randomized controlled trials of over 2000 patients with New York Heart Association (NYHA) class 2 to 4 heart failure. These studies were stopped after 5.7 and 12 months, respectively, for failure to show any improvement in survival, hospitalizations, or NYHA class [48]. Although no benefit was seen, several patients did experience adverse cardiac outcomes, even those with NYHA class 2 disease. Infliximab has also been tested in 150 patients with NYHA class 3 and 4 disease. This trial was prematurely discontinued at 28 weeks for a dose-related increase in hospitalizations and deaths [49]. A recent FDA analysis of postmarketing congestive heart failure events disclosed 51 patients who were receiving etanercept or infliximab; 42 of these patients presented with new-onset congestive heart failure [32], and half of these patients had no known risk factors. Thus it appears there is a rare and unknown association with new-onset congestive heart failure. Patients with a history of NYHA class II, III, or IV heart failure should consider using other therapies before starting on TNF inhibitors. Patients with heart failure who are currently receiving TNF inhibitors should be warned of these risks and should have their cardiac status monitored closely. Malignancy and lymphoma All three marketed TNF inhibitors—etanercept, infliximab, and adalimumab— have been evaluated for their effect on neoplasia [18]. A 2003 FDA panel focused specifically on the issue of lymphoma in RA patients receiving TNF blockers. Past studies have generally shown that RA patients are not at risk for malignancy, particularly in the case of solid tumors, and may be at a lower risk of adenocarcinoma of the colon. However, population studies have shown a two- to threefold increased rate of lymphoma and non-Hodgkin’s lymphoma in RA patients [18]. It has also been shown that the lymphoma risk increases with increasing inflammatory disease activity and RA functional class [50]. In the recent FDA analysis the observed number of malignancies in patients treated with etanercept, infliximab, and adalimumab was equal to that expected from the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. In contrast, six lymphomas were found among 6303 RA patients in controlled clinical trials, but none were observed in placebo-treated patients. In both the randomized, placebo-controlled trials and open-label follow-up of the same patients, a total of 23 lymphomas was observed (9 etanercept, 4 infliximab, 10 adalimumab) with an increased relative risk of 3.47, 6.35, and 5.42, respectively [18]. Unfortunately the 95% confidence intervals for these standard in-

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cidence ratios was particularly wide and overlapping (range: 1.59– 16.3), thereby not permitting any separation of lymphoma risk between drug or active RA alone. Thus lymphoma rates in RA patients taking TNF inhibitors are elevated, but it is not yet known if this represents an excessive risk (above that incurred by the disease) when TNF inhibitors are used. In postmarketing surveillance of over 515,000 RA patients worldwide, nearly 160 developed lymphoma [7]. The crude occurrence rate in the postmarketing era is roughly two to three cases per 10,000 patient years of drug exposure, a rate that approximates that seen in the general population. The latency from TNF blocker exposure to the onset of lymphoma varied widely, but the majority occurred between 6 and 24 months. Hodgkin’s lymphoma was seen in 15% of cases, and the remaining were nonHodgkin’s lymphomas usually of the diffuse large B cell class. Follicular, mantle, mucosa-associated lymphoid tissue, and T cell lymphomas were uncommonly observed. Anakinra use has rarely been associated with the development of lymphoma or other cancers and is without specific pattern to suggest an association [2]. Drug-induced lupus The induction of autoimmunity (autoantibodies, lupus-like disease) by TNF inhibitor use was first observed in randomized clinical trials with lenercept, a P55 receptor– immunoglobulin construct whose development was halted for efficacy and toxicity reasons [51]. Subsequent clinical trials in other TNF inhibitors have also yielded similar events. These findings were uncommon and were also unexpected based on preclinical or animal models. Some investigators have suggested that levels of TNF-a expression may favor the development of autoreactivity in susceptible individuals [52]. Interestingly, infliximab infusion has been associated with a paradoxical rise in IL-10 [53], a regulatory antiinflammatory cytokine that is also known to stimulate humoral activity. The exact mechanism through which TNF inhibition may promote autoimmunity and in whom is currently unclear. Antinuclear antibody (ANA) positivity is commonly found in 30% to 40% of RA patients, regardless of a history of DMARD use. When RA patients were treated in controlled clinical trials, the incidence of new ANA positivity ranged from 11% in those patients treated with etanercept, 12.9% in those treated with adalimumab, and 26% to 49% in those treated with infliximab [3 – 5]. However, ANA positivity has little or no pathogenic significance in these patients. Possibly of greater concern is the occurrence of native (or double-stranded) DNA antibodies, found in 3% to 15% of etanercept-treated patients, 8% to 15% of infliximab-treated patients, and 5.6% of adalimumab-treated patients. Despite these impressive numbers, the incidence of TNF inhibitor– related drug-induced lupus is rare. Thus out of 1897 infliximab treated patients there were only four reports of a lupuslike disease (0.2%) [54]. Although there were no reports of drug-induced lupus in the etanercept clinical trial patients, there have subsequently been several reports in the postmarketing era [55]. Rare cases of lupuslike disease were

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also noted with lenercept and adalimumab [32,51]. To date, over 22 cases of drug-induced lupus have reported following the use of a TNF inhibitor [19,32, 51,54 – 63]. Based on these limited reports, the profile of patients receiving a TNF inhibitor who develop a lupuslike disease appears to be well defined (Table 3). This syndrome has been reported in patients with well-established RA, juvenile RA, and Crohn’s disease, and at the time of lupus onset all appeared to be responding well to therapy. The usual interval before lupus onset is variable, but onset most often occurs within 4 to 8 months of starting therapy. The most common lupus presentations include rash, serositis, acute polyarthritis, or cytopenias (including leucopenia, lymphopenia, thrombocytopenia, and hemolytic anemia). As with other cases of drug-induced lupus, renal or neurologic manifestations have not been observed. Interestingly, many patients developed an acute flare with polyarthritis affecting the hands, wrists, elbows, shoulders, knees, or ankles. Few have reported myalgias and a rare case of muscle enzyme elevation without weakness has been seen [58]. A variety of cutaneous manifestations have been reported, but only a minority of these were malar rashes. Several cases presented with an acute erythematous rash with the appearance of an acute ‘‘sunburn’’ with erythema (± scale) overlying the face and upper extremities. Other rashes have been deTable 3 Profile of 22 patients with drug-induced lupus due to TNF inhibitor Median age Sex Indication for use TNF inhibitor Prior history of lupus features TNF exposure to lupus onset Fever Serositis Cytopenia Arthritis Rash Rash descriptors ANA ANA pattern DNA Low complement Antiphospholipid antibodies Antihistone antibodies Other test abnormalities Treatment Time to resolution

50 years (range: 12 – 70) >80% female 3 CD; 2 JRA; 17 RA 9 infliximab, 9 etanercept, 1 adalimumab 1 /2 ANA+, 2 lymphopenia, 1 each with DNA+, low C4, history of DLE Median 5 mo (2 wk – 17 mo) 2/13 patients 5/19 patients 3/19 patients 7/19 patients 12/19 patients Malar 4, sunburn 4, photosensitive 3, facial 3, urticarial 3, purpuric 100% (1:160 to >1:10,240) Homogeneous or speckled 80% 5/19 patients 2 patients (one with coronary thrombosis) 6 patients — Discontinuation; topical steroids; prednisone 10 – 60 mg daily All resolved, 3 – 8 wk

Abbreviations: ANA, antinuclear antibody; CD, Crohn’s disease; JRA, juvenile rheumatoid arthritis; RA, rheumatoid arthritis; TNF, tumor necrosis factor. Data from Refs. [19,32,52,55 – 64].

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scribed as facial, discoid or subacute cutaneous lupus, vasculitic, urticarial, or purpuric. Several cases have shown characteristic biopsy changes of lupus skin disease; a few cases had a positive lupus band test. Many of the reported cases had exhibited a lupuslike feature before TNF therapy, usually in the form of a low-titer positive ANA. Nonetheless, all patients who developed this syndrome were ANA positive, and the majority also had antibodies to dsDNA. Other autoantibodies against Sm, RNP, histone, and cardiolipin have been observed less frequently. All cases resolved when the TNF inhibitor was withdrawn, and some required topical or systemic corticosteroids (eg, prednisone 10 – 60 mg/d). Time to resolution varied, but many patients were notably improved within 4 to 8 weeks of drug discontinuation. However, serologic abnormalities may persist for 6 months or more. Baseline or ongoing monitoring of ANA, native DNA, or other autoantibodies in patients receiving anti-TNF therapy is not advised. Although more than half of patients with a lupuslike syndrome had a history of a lupus features (ANA positivity, lymphopenia, discoid lupus erythematosus, and so forth), clinical trials have shown that ANA (and even DNA) serologic findings changed frequently and were not predictive of response, toxicity, or autoimmune toxicities. However, serologies may be indicated in patients who exhibit an unexpected flare of their arthritis, fever, serositis, or rash. It also appears that RA patients who are ANA positive may safely receive TNF inhibitors without a substantial risk of further autoimmune disease. Anecdotally, TNF inhibitors have been used in few lupus patients with problematic inflammatory synovitis without worsening of other lupus features. However, a recent abstract suggests lupus patients may have more infliximab infusion – related reactions [64] Hepatotoxicity Recent FDA postmarketing surveillance unexpectedly revealed 134 spontaneous reports of liver failure associated with TNF inhibitor use [31]. In a detailed review of 50 cases receiving either infliximab or etanercept, confounding diagnosis or hepatoxin exposure was seen in 43 cases (eg, sepsis, TB, isoniazid use, alcohol, viral hepatitis, graft versus host disease, hepatotoxic drugs). However, in seven cases no other cause could be identified, suggesting that TNF inhibitor use may have lead to hepatic failure. In the clinical trials with infliximab and adalimumab, sporadic two- to threefold liver function test elevations may have been attributed to TNF inhibitor. Clinicians should be aware of these rare events and report similar findings to the FDA at www.medwatch.com. Pregnancy There are no controlled trials of TNF inhibitors in pregnant women. There is little available information on the use of TNF inhibitors in women who are or may become pregnant. Infliximab, adalimumab, and etanercept are a category ‘‘B’’ pregnancy risk because there are no controlled studies in pregnant women. Antoni and colleagues [65] have reported on the postmarketing experience of

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infliximab use associated with 59 pregnancy conceptions, including 16 patients who received the drug during the first trimester. Seventy-two percent of the patients had live births, 14% had miscarriages, and 14% had elective terminations. One live birth was a preterm, low – birth weight death and another had Tetrology of Fallot that was successfully repaired. Overall, these outcomes were similar to a national cohort of healthy women, suggesting that infliximab may not have altered pregnancy outcomes in this observational study. Further research in this area is needed.

Summary The use of novel DMARDs (leflunomide, anakinra, TNF inhibitors) has produced newfound levels of patient satisfaction. The toxicities detailed herein are often mild to moderate, often resolve or are well tolerated, and seldom warrant discontinuation of the drug. Serious and potentially life-threatening adverse events are rare, even in the postmarketing era. Clinicians should be mindful of these rare adverse events (eg, tuberculosis or lymphoma) and should counsel patients appropriately based on their concerns and quality of life. Because many of these serious toxicities occur at rates of 1 or fewer cases per 1000 patient years of use, it appears that proper patient selection and prevention measures are needed to further limit this risk.

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