Heart Failure and Drug-Induced Lupus

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

J.J. Cush

John J. Cush, MD, Chief, Rheumatology ABSTRACT demyelinating disease, cytopenias, auto- and Clinical Immunology, Presbyterian Serious and unexpected adverse events, immune disorders, and heart failure. Hospital of Dallas, Clinical Professor of such as heart failure and drug-induced Other essays in this volume address the Internal Medicine, The University of Texas lupus, have been reported in patients subject of infection (10), demyelination Southwestern Medical School, Dallas, Texas, USA. receiving TNF inhibitor therapy. These (11), and lymphoma (12). This review events generally are easily recogniz- will focus on heart failure and lupus- Please address correspondence to: John J. Cush, MD, Presbyterian Hospital able, although they cannot be predicted like disease, which are rarely seen in of Dallas, 8200 Walnut Hill Lane, Dallas, nor avoided, other than by drug avoid- association with TNF inhibitor therapy Texax 75231-4496, USA. ance altogether. Many patients have and are currently without explanation. Clin Exp Rheumatol 2004; 22 (Suppl. 35): great benefit from anti-TNF therapies. S141-S147. Their intelligent use requires a firm Sources of data © Copyright CLINICAL AND EXPERIMENTAL understanding of these rare toxicities, As a consequence of drug approval, RHEUMATOLOGY 2004. so as to minimize the morbidity associ- manufacturers have a responsibility to ated with their uncommon occurrence. collect safety data actively and report Key words: TNF inhibitors, conges- these data to the appropriate agencies. tive heart failure, drug-induced lupus, Introduction For example, in the USA a manufactur- rheumatoid arthritis. The introduction of biologic agents to er must submit periodic safety reports specifically inhibit the pro-inflammato- to the FDA twice yearly (March and ry cytokine, tumor necrosis factor (TNF), September). Moreover, other parties has transformed traditional treatment are also focused on the safety of TNF paradigms for a wide range of inflam- inhibitors. These include the drug man- matory disorders. Many patients with ufacturer (each having its own global rheumatoid arthritis (RA), Crohn's coli- safety/pharmacovigilance office), regu- tis, psoriasis and a variety of spondyl- latory agencies (e.g., FDA, EMEA [Eu- oarthropathies have been afforded new- ropean Agency for the Evaluation of found disease control, especially when Medical Products]), external individu- traditional agents have failed, were only als, researchers, clinicians and patient partially effective, or were not tolerat- advocacy groups which may report ad- ed. After 6 years of use, these drugs have ditional safety data or have access to been administered to nearly 700,000 publically available drug safety reports. patients worldwide, although only a When analyzing the safety of TNF inhi- minority of patients with inflammatory bitors, data are collected from the FDA's diseases have received them. The re- Medwatch/AERS (Adverse Event Re- strained growth of this class of therapy porting System), specific freedom of is affected by high costs, limited num- information (FOI) requests for safety bers of ideal candidates, lack of clear reports, review of the medical litera- guidelines for use and a continued con- ture, and scientific abstracts and com- cern for their long-term safety (1,2). posite data derived from national and The most common toxicities seen with international patient registries (9). these agents were defined during con- Each of the manufacturers of TNF in- trolled clinical trials and drug develop- hibitors have committed itself to multi- ment (3-5). However, following FDA ple, large on-going open-label safety approval, post-marketing surveillance registries to further discern the true has disclosed a number of rare or un- incidences of rare or unusual events. Of- usual signals that underscore the need ten causality can be difficult to define, for further large, population-based stu- as many of these events could be as- dies concerning the safety of TNF in- cribed to the disorder under treatment, hibitors (6-9). These rare and unusual rather than to the treatment alone. A events include opportunistic infections, prolonged period of at least 5-10 years serious infections, possible lymphoma, is required to distinguish between two

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Table I. Adverse outcomes in CHF treated with TNF inhibitors+ (8).

Study name RENAISSANCE RECOVER ATTACH

TNF inhibitor Etanercept Etanercept Infliximab

N (NYHA Class) 925 (NYHC 2-4) 1123 (NYHC 2-4) 150 (NYHC 3-4)

Regimens Placebo, Placebo Placebo 25 mg BIW, TIW 25 mg BIW 5 mg/kg or 10 mg/kg @ weeks 0, 2 & 6

Study duration Median 12.7 mos. Median 5.7 mos 28 weeks

Death rates* Placebo 14.2% Placebo 8.8% Placebo 5 mg/kg 10 mg/kg ETAN BIW 17.9% ETAN QWK 5.9% @wk 28 0 2.0% 5.9% ETAN TIW 19.8% ETAN BIW 7.2% @wk 54 8.2% 8.0% 15.7%

CHF* NA NA Placebo 5 mg/kg 10 mg/kg hospitalization @wk 28 10.2% 6.0% 21.6%

Concerns ? TIW dose group more problems. 10 mg/kg @ higher risk NYHA Class II are NOT at lower risk

+All studies were prematurely halted for futility or poor outcomes; *at the end of study. large populations (>10,000) of treated creased circulating levels of TNF in pa- had entry ejection fractions of 22-24%. and untreated patients, and these com- tients with congestive heart failure Most were NYHA Class 3 (70-72%), parisons are confounded by the fact (CHF), especially in those with NYHA with some being NYHA Class 2 (24- that patients who are treated with bio- class III and IV disease that is associat- 27%) These studies were discontinued logic agents are likely to have a more ed with severity and higher mortality after 12 and 5.7 months respectively severe clinical status. Finally, when risk. Transgenic mice which overex- for "futility"; defined as less than 10% post-marketing analyses yielded unex- press TNF have dilated cardiomyopa- benefit in morbidity or mortality end- pected or serious safety signals, the FDA thy and premature death. These data points (CHF hospitalizations, death has twice initiated public proceedings led many investigators to an a priori rates, improvement in NHYA class, to examine the safety of TNF inhibitors assumption that TNF inhibition would patient global assessment). in clinical practice. These proceedings improve cardiac function and survival While no benefit was seen, several pa- have been published elsewhere as part in patients with CHF (11). tients did experience adverse cardiac of the American College of Rheumatol- Clinical trials with both etanercept and outcomes, even those with NYHA class ogy (ACR) Hotline series (6-9). infliximab were initiated in patients 2 disease. The multi-national RECOV- with heart failure who did not have ER trial did not show benefit or wors- TNF and heart failure arthritis or inflammatory diseases (14- ening using conventional dosing of 25 TNF has been presumed to play a cru- 16). After 6-12 months of study these mg weekly or twice weekly. The North cial role in the pathogenesis of heart trials were halted prematurely due to American RENNAISSANCE trial show- failure and cardiac cachexia (2, 13). the absence of effect and/or poorer out- ed a non-signifcant trend toward more Systemic effects of TNF, IL-1 and oth- comes (8, 9). Reasons for the absence flares of CHF and hospitalization in er proinflammatory cytokines are well of anticipated benefit with either drug, those treated with higher doses of etan- known causes of anorexia, cardiac ca- or for the paradoxical outcomes seen in ercept, 25 mg thrice weekly. It is not chexia, endotoxic shock, etc. These cy- patients on higher doses of etanercept known if the premature cessation of tokines may also have untoward vascu- or infliximab, are not understood. these trials may have masked further lar effects by promoting the expression Table I summarizes the clinical trials cardiac risks associated with etanercept of adhesion molecules and alterations that were reviewed at a March 2003 therapy. in blood flow (13). TNF has been shown FDA conference concerning the safety Infliximab was also studied in a pilot, to have negative inotropic effects on of TNF inhibitors (8,9). Etanercept was phase II trial of 150 RA patients (8, 9, the myocardium and may further con- studied in two randomized controlled 16). This North American, placebo- tribute to left ventricular dysfunction trials (RENNAISSANCE and RECO- controlled trial involved NYHA class 3 and cardiomyopathy. TNF also causes VER trials) involving 2,048 patients and 4 CHF patients. Patients were ran- myocyte dysfunction and death, and with NYHA class 2-4 heart failure (14, domized to receive 3 infusions of pla- may cause myocardial fibrosis and al- 15). These patients had a history of cebo or 5mg/kg or 10mg/kg infliximab teration of myocardial matrix proteins CHF for a mean of 4.6 to 5.6 years, over 6 weeks and were then followed. to contribute further to the myocardial were predominantly male (78%), Cau- This study was discontinued after an in- failure. Several studies have shown in- casian (84-99%), 62-65 yrs old, and terim analysis at week 28 (TableI) indi-

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Heart failure and drug-induced lupus in TNF inhibition / J.J. Cush cated that CHF hospitalizations and adalimumab treated patients (N=1362) identified incident cases of heart failure deaths were higher in the 10 mg/kg in- and 0.5% in placebo-treated patients (N in 13,171 RA patients receiving TNF fliximab treated group (21.6% hospital- = 683). Therefore, in the randomized inhibitors and other DMARDs (17). In izations, 5.9% deaths), compared with controlled trials of all 3 TNF inhibitors their study, heart failure was more the placebo treated group (10.2% hospi- involving more than 7,300 patients, a common in RA patients (3.9%) than in talizations, no deaths). When these pa- total of 18 new onset CHF reports have those with osteoarthritis (2.3%). Among tients were followed for 54 weeks, 4 emerged; 7 occurring with use of TNF RA patients, those who received TNF deaths were noted in the placebo and 5 inhibitors (< 0.2%) and 11 with the use inhibitors had fewer episodes of heart mg/kg groups, while 8 deaths were of placebo (0.7 Ð 2.1%). Thus, review failure (3.1%) than those receiving oth- seen in the 10 mg/kg treatment group. of these clinical trial data suggests that er DMARDs (3.8%). Moreover, those These results prompted a change in the risk of TNF inhibitor-associated RA patients without evidence of prior product label and an October 2001 heart failure in RA patients without heart disease were at very low risk for "Dear Doctor" letter warning clinicians background heart disease is substan- CHF, regardless of whether they had of this association. tially different than when these drugs received TNF inhibitors or not. Simi- are given to patients who have heart larly, Lenart et al. has reported an anal- Heart failure in RA patients failure alone. ysis of a South Swedish Registry that Over the last few years it has become compared 412 TNF inhibitor-treated increasingly clear that the increased CHF post-marketing safety reports RA registry patients with 580 RA mortality rates seen in RA are partly The FDA has reviewed spontaneous patients (control group) and showed a due to augmented rates of cardiovascu- reports from the Medwatch (AERS) lower incidence of cardiovascular events lar events stemming from the damag- system and disclosed 158 spontaneous among TNF-treated patients (14 events ing vascular effects of systemic inflam- reports of CHF associated with the use in 667 person-years or 2.1%) than con- mation (2, 13). These data affirm that of TNF inhibitors (8, 9). A more exten- trols (123 events in 2303 person-years RA patients are at increased risk for sive analysis of 51 of these patients was or 5.3%) (18). The age-adjusted inci- developing cardiac disease. Analysis of performed. The study group comprised dence rates per 1000 person-years were TNF inhibitor-treated RA patients, 30 patients treated with etanercept, 21 28.5 for controls, but only 0.57 in TNF especially those without a prior history with infliximab, and none on adali- inhibitor-treated RA patients. They of CHF, recent myocardial infarction or mumab, (the analysis was performed concluded that the effective control of uncontrolled hypertension, may clarify prior to drug approval). There were 9 inflammation may in fact lower the risk further the risk of heart failure when exacerbations of pre-existing CHF, and of cardiovascular disease in RA (18). using these agents. 42 cases of new onset CHF. Among the RA patients without a history of signif- new onset cases, half had no prior risk Practical considerations concerning icant cardiovascular disease were stud- factors. The mean age was 64 years and the use of TNF inhibitors with CHF ied during pivotal phase II and III clin- the median time to onset was 3.5 It appears that a rare and unknown as- ical trials for all three TNF inhibitors months (range 1 day to 2 yrs). Three sociation may exist between TNF in- (3-5, 9) (Table II). With each drug there deaths occurred. Ten of the 51 patients hibitor use and new onset CHF. While was no increase in the number of CHF who developed CHF (4 etanercept, 6 data from the CHF trials suggest not flares or de novo cases. In the etaner- infliximab) were less than 50 years of only no cardiac benefit, but also poten- cept RA clinical trials involving 3,389 age. Three had known risk factors. The tial hazardous consequences of TNF patients, new-onset CHF occurred in median ejection fraction was 20%. All inhibitor use, especially with higher only 2 placebo-treated and 2 etaner- stopped anti-TNF therapy: 3 resolved, doses, use of anti-TNF in patients with cept-treated patients. Analysis of more 6 partially improved and 1 patient died. RA does not appear to contribute to than 1,600 RA patients treated in con- Following this FDA review, several incident CHF. Whether TNF inhibitors trolled clinical trials indicated that new publications have addressed the inci- can safely be used in patients with RA onset CHF occurred in 0.2% of inflix- dence of heart failure among RA pa- and other inflammatory disorders who imab and 2.1% of placebo-treated RA tients treated with TNF inhibitors. For have pre-existing CHF has not been and Crohn's disease patients. During example, Michaud and Wolfe have re- objectively studied. Until further stud- the adalimumab clinical trials, the inci- ported the results of a National Data ies become available, it may be prudent dence of new onset CHF was 0.1% for Bank for Rheumatic Disease study that to avoid initiation of TNF inhibitors in patients with pre-existing NYHA Class Table II. New onset heart failure during clinical trials of TNF inhibitors in RA. III or IV disease or unstable heart failure. RA patients whose heart failure is Etanercept Infliximab Adalimumab well controlled and those who are cur- (n = 3,389) (n > 1,600) (n = 2,045) rently receiving TNF inhibitors should Active drug 2 0.2% 0.1% be told of these risks and have their car- Placebo 2 2.1% 0.5% diac status monitored closely.

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Table III. Analysis of 51 patients with new onset CHF in RA. ANA positivity or drug-induced lupus are unknown (20-24), and the pathogenesis of autoimmunity in the context of a TNF-deficient state remains unknown. In addition to its proinflammatory effects, TNF functions as an im- munoregulatory B cell growth factor. It also affects multiple cell types, including dentritic cells that may alter B cell activity (23). TNF serum levels are increased in patients with lupus, as are tissue concentrations in the kidneys Mean age = 64 yrs (24). While it appears that TNF may Median onset from TNF to CHF = 3.5 mos (24 h Ð 2 yrs) play a contributory role in human lu- 3 deaths pus, data from murine models of lupus 20% (10) CHF pts < 50 yrs 6 infliximab & 4 etanercept indicated that TNF may contribute to Ejection fraction = 20% disease progression in NZB/NZW mice, 3 with CHF risk factors while a paradoxical beneficial effect is all d/c TNF @ CHF Dx observed in the MRL mouse (23, 25). 3 resolved 6 improved Moreover, TNF may play paradoxical 1 death roles at different time points in matura- tion. Table IV. Frequency of autoantibodies and drug-induced lupus during TNF inhibitor clini- Extrapolation of these data to humans cal trials+. with RA or systemic lupus is further confounded since a weak TNF inhi- ANA(+) dsDNA(+) Drug-induced lupus bitor, thalidomide, has been reported to Rheumatoid arthritis 30-40% 0-4% NA improve joint disease in RA and skin Lenercept 13% 3% NA disease in SLE, without autoimmune Infliximab 52% 17% 3/1678 flares or new serologic abnormalities. Etanercept 11% 15% 0/ Nonetheless, some investigators have α Adalimumab 12.9% 5.6% 1/2334 suggested that levels of TNF expression may favor the development of au- + Frequencies derived from package insert for each agent; data from phase II and III clinical trials prior toreactivity in susceptible individuals. to drug approval. In each instance, autoantibody frequency was greater than placebo control patients It has been shown that following inflix- (from refs 3-5). imab infusion, there may be a paradoxical rise in IL-10 levels (26). While IL- TNF inhibitors, autoantibodies ANA tests (and vice versa) was seen 10 exhibits anti-inflammatory effects, and drug-induced lupus more commonly in those receiving TNF it is also well known to stimulate hu- The occurrence of autoimmunity in inhibitors than in the control patients. moral activity, and may promote the en- patients receiving TNF inhibition was The incidence of new ANA positivity hanced autoantibody production seen first described during clinical trials was 26-62% with infliximab, 11% with with therapeutic TNF inhibition. with lenercept, a soluble p55 receptor etanercept and 12% with adalimumab. construct that bound TNFα (19). ANA The incidence of new dsDNA antibod- How common is drug-induced lupus? positivity (13%) and dsDNA antibodies ies was 15% for infliximab and etaner- Drug-induced lupus is defined as the (3%) were observed in a 247 patient tri- cept and 5.9% for adalimumab. In a stu- new occurrence of a lupus-specific fea- al wherein lenercept was effective, but dy of 156 infliximab treated patients, ture (e.g., serositis, cytopenia, arthritis) was not shown to be more effective Charles et al. found low titers of predo- in the context of ANA positivity, and than MTX alone. Subsequent develop- minantly IgM anti-dsDNA antibodies with the resolution of symptoms upon ment of other TNF inhibitors has indi- in 7% of patients (20). Only one patient withdrawal of the offending agent. Al- cated variable percentages of autoanti- (0.64%) developed drug-induced lupus though the time to clinical improve- bodies (Table IV). While ANA and ds- with fever, rash, pleuropericarditis and ment is often rapid and related to the DNA antibody positivity was not un- arthritis flare; this patient also had IgG half-life of the drug, the time to be- common, overt drug-induced lupus was and IgA anti-dsDNA antibodies. come ANA negative generally is more rarely observed (2-5). prolonged and may require up to 12 During clinical trials, these autoantibo- Pathogenesis of TNF-induced months to fully resolve (27). dies were commonly recorded and ser- autoimmunity Overall, the risk of developing drug- oconversion from negative to positive The etiology of the development of induced lupus from TNF inhibitor use

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Table V. New drug-induced lupus associated with TNF inhibitors in Dallas, Texas. induced lupus associated with TNF inhibitor therapy (28-32). The profile Patient 1 2 3 4 of patients developing a lupus-like disease is described in Table VI. Most pa- Age/Sex 35F 26F 44F 63F tients appear to have an acute onset of Indication RA RA Crohn's RA mild to moderate lupus manifestations TNF inhibitor Infliximab Infliximab Infliximab Etanercept that may include constitutional fea- Lag time (months) 23 14 3 1.8 tures, fever, polyarthritis, serositis, 1st Symptom Pericarditis Fever, rash Arthritis Pleuritis rashes or cytopenias. While arthalgias Arthritis 0 Poly Poly 0 and myalgias were common, the new Serositis ++ + 0 + onset of both large and small joint Cytopenia Lymphopenia 0 0 Lymphopenia polysynovitis was seen in roughly one- ACR criteria 4 5 2 4 third of drug-induced cases. The occur- Resolved ? Yes, 4 wks Yes, 4 wks Yes, 6 wks Yes, 6 mos rence of an acute flare of polyarthritis in a patient with RA who is well con- Table VI. Manifestations of anti-TNF associated drug-induced lupus (27). trolled on a TNF inhibitor should raise suspicion for drug-induced lupus and Cush 2004 DeBandt 2004 Dallas (unpublished) prompt appropriate evaluation and testing. No. 22 12 4 Early reports suggested that discoid or Female > 80% 100% 100% subacute cutaneous lupus or purpuric Inflix/Etan/Ada I-9 E-9 A-1 I-9 E-3 I-3 E-1 lesions (hypersensitivity vasculitis) were No. of SLE criteria ND All > 4 4, 5, 2, 4 common cutaneous presentations. How- Prior ANA(+) 50% 3/12 1/4 ever, a wider spectrum of findings has Onset lag time 2 wks Ð 17mos Mean = 8 mos. 1.8 Ð 23 mos been described, including facial and Arthritis 5/19 5/12 2/4 malar rashes, an acute "sunburn" in- Serositis 5/19 3/12 2/4 tense erythema over the face, trunk or Fever 2/13 9/12 constitutional 2/4 extremities, and urticaria. Alopecia and Cutaneous 12/19 11/12 1/4 new onset Raynaud's phenomenon Cytopenias 3/19 12/12 2/4 have not been described. Serositis, in- ANA + 100% 100% 100% volving the pleural or pericardial mem- Anti-dsDNA ~80% 11/12 2/4 branes, has been seen in up to one-third Low complement 5/19 ND 2/4 of patients. Fever and elevated acute Mean time to resolution 3-8% 8 weeks 4-6 weeks phase reactants are seen in a minority Negative rechallenge* ND 3 Etanercept 1 Adalimumab of patients, and appear to correlate with serositis, acute inflammatory arthritis, *Patients were rechallenged with the offending TNF inhibitor without recurrence of lupus-like disease. and autoantibodies. There have been no clinical reports of the nephritis, cerebri- appears to be quite low, with only 4 re- patients met only 3 lupus criteria while tis, or the antiphospholipid syndrome. ports among 1,897 infliximab-treated the remaining 12 met 4 or more crite- While ANA positivity is required for patients (0.2%) (28). Although there ria. These investigators estimated the diagnosis, many patients also exhibit were no reports of drug-induced lupus prevalence of lupus associated with other autoantibodies including rheuma- in etanercept clinical trial patients, there TNF inhibitors to be 1.7 events per toid factor, anti-dsDNA antibodies, and have subsequently been several reports 1000 patients Ð a rate similar to that other antibodies directed against Sm, in the post-marketing era (29). Rare reported above in the infliximab trials. RNP, histone and cardiolipin. Hypo- cases of lupus-like disease were also Finally, a review by Callegari et al. of complementemia has been observed noted with adalimumab (9). A recent FDA safety data accumulated up to less frequently. Confirmation of the di- review of this problem disclosed 22 re- March 2002 identified 59 infliximab- agnosis rests with the resolution of ports in the medical literature (30). and 16 etanercept-treated patients with lupus-like manifestations upon with Table V details 4 new patients recently drug-induced lupus. The calculated in- withdrawal of the offending TNF inhi- identified in Dallas (unpublished ob- cidence rates were 0.13 and 0.29 per bitor. The time to resolve symptoms servation, S. Cohen, G.A. Quiceno, J. 1000 patients, respectively (32). ranges from 3-8 weeks in most pa- Cush). tients, and may to be related to the half- A recent EULAR abstract identified 22 Lupus-like manifestations life of the agent. Monitoring of autoan- new cases of drug-induced lupus after While there may be some duplicate re- tibodies in clinical practice is not rec- treatment with TNF inhibitors among a porting of the same patients, there ap- ommended in current prescribing cohort of RA patients (31). Ten of these pear to be more than 100 cases of drug- guidelines, although their identification

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Heart failure and drug-induced lupus in TNF inhibition / J.J. Cush may be necessary in anti-TNF-treated 2) the prevalence of ANA positivity gy, 3rd ed., Edinburg, Mosby, 2003; 461-84. patients who exhibit a flare of their (12-62%) and DNA positivity (5-15%) 3. Etanercept package insert. 4. Infliximab package insert. arthritis, unexplained rashes, serositis, (Table IV); 3) murine models that im- 5. Adalimumab package insert. fever, or other clinical signs which sug- plicate TNF inhibition with poorer out- 6. CUSH JJ, MATTESON E: FDA advisory com- gest drug-induced lupus comes; and 4) rare suggestion (without mittee reviews safety of TNF inhibitors. Hot- proof) of de novo SLE following TNF line American College of Rheumatology, Sep- tember 2001. http://www.rheumatology.org/ Management of drug-induced lupus inhibition. research/hotline/0901tnf.html Baseline testing and ongoing monitor- These observations are countered by 7. CUSH JJ. KAVANAUGH AF: FDA Meeting ing of ANA, native DNA or other auto- other data which nullify their impact. March 2003: Update on the safety of new antibodies in patients who are receiv- First, up to 40% of RA patients are drugs for rheumatoid arthritis. Part I: The risk of lymphoma with rheumatoid arthritis (RA) ing anti-TNF therapy is not advised ANA-positive, and that such a finding and TNF inhibitors. Hotline. American Col- and not required by prescribing guide- has no known influence on disease lege of Rheumatology. April 2003 http:// lines (2,13,30). Some patients reported expression or toxicity risk. Second, in www.rheumatology.org/research/hotline/ to develop a lupus-like syndrome while several thousand patients who were 0303TNFL.htm 8. KAVANAUGH AF, MATTESON E, CUSH JJ: receiving a TNF inhibitor had a history treated in double-blind clinical trials, FDA Meeting March 2003: Update on the of a lupus-like feature, ANA positivity, use of a TNF inhibitor in ANA + RA safety of new drugs for rheumatoid arthritis. lymphopenia, DLE, Sjögrens syn- patients did not lead to greater serolog- Part II: CHF, infection and other safety is- sues. Hotline American College of Rheuma- drome etc., Clinical trials have shown ic positivity, more autoimmune events, tology, August 2003. that ANA (and even DNA) serologic or cases of drug-induced lupus. Al- 9. ARTHRITIS ADVISTORY COMMITTEE: FDA findings changed frequently from posi- though drugs like procainamide, quini- Briefing document, March 2003. http://www. tive to negative and were not predictive dine, or minocycline may induce sero- fda.gov/ohrms/dockets/ac/acmenu.htm 10. BIEBER J, KAVANAUGH A: Tuberculosis and of response, toxicity or autoimmune logic changes or (rarely) drug-induced opportunistic infections: relevance to biolog- toxicities. It also appears that RA pa- lupus, they are not contraindicated in ic agents. Clin Exp Rheumatol 2004; 22 (Sup- tients who are ANA-positive may safe- patients with lupus or other autoim- pl. 35): S127-S133. ly receive TNF inhibitors without a mune diseases. Finally, lupus patients 11. MAGNANO M, ROBINSON WH, GENOVESE MC: Demyelination and the use of TNF inhi- substantial risk of further autoimmune have antecdotally been treated with bition. Clin Exp Rheumatol 2004; 22 (Suppl. disease. Anecdotally, TNF inhibitors TNF inhibitors without compromise and 35): S132-S140. have been used in lupus patients who often with great benefit. The author 12. VAN VOLLENHOVEN RF: Benefits and risks of had problematic inflammatory synovi- has treated 2 SLE patients with prob- biological agents: Lymphomas. Clin Exp Rheu- matol 2004; 22 (Suppl. 35): S122-S125. tis, with improvement in synovitis and lematic synovitis with TNF inhibitors, 13. KHANNA D, MCMAHON M, FURST DL: without worsening of other lupus fea- with good results and no flare of their Anti-tumor necrosis factor alpha therapy and tures (see below). The author is aware lupus. At the 2004 EULAR meeting, heart failure: what have we learned and where do we go from here ? Arthritis Rheum 2004; of 4 patients who developed TNF in- Aringer and Smolen reported that lupus 50: 1040-50. hibitor-associated drug-induced lupus activity, measured by SLEDAI, and 14. ANKER SD, COATS AJ: How to RECOVER who were later rechallenged with the arthritis improved in all of 6 lupus pa- from RENAISSANCE ? The significance of the same or a different agent without recur- tients treated with intravenous inflix- results of RECOVER, RENAISSANCE, RENEW- AL and ATTACH. Int J Cardiol 2002; 86: 123- rence (Table VI). Nonetheless, a cau- imab 300 mg at weeks 0, 2, 6, and 10 30. tionary report indicates that 2 patients (34). Four patients with nephrotic syn- 15. MANN DL, MCMURRAY JJ, PACKER M et al.: who had RNP + MCTD received either drome showed significant improve- Targeted anticytokine therapy in patients with etanercept or infliximab and later flar- ment in proteinuria. Although dsDNA chronic heart failure: results of the Random- ized Etanercept Worldwide Evaluation (RE- ed with arthralgias, myalgias, rash, fe- antibodies were found in 4 patients, all NEWAL). Circulation 2004; 109: 1594-602. vers (33). demonstrated elevated or normal com- 16. CHUNG ES, PACKER M, LO KH, FASANMADE plement levels. No flare of lupus activ- AA, WILLERSON JT and the ANTI-TNF THER- Can TNF inhibitor therapy be used ity and no serious adverse events or APY AGAINST CONGESTIVE HEART FAILURE INVESTIGATORS: Randomized, double-blind, in lupus? infusion reactions were seen Although placebo-controlled, pilot trial of infliximab, a Lupus, multiple sclerosis (MS) and de- this pilot trial lends support to the pos- chimeric monoclonal antibody to tumor myelinating disorders are currently re- sibility that ant-TNF therapy may be necrosis factor-alpha, in patients with moder- garded as relative contraindications for safe and effective in lupus, further con- ate-to-severe heart failure: results of the anti- TNF Therapy Against Congestive Heart Fail- the use of these agents. However the trolled clinical trials are required before ure (ATTACH) trial. Circulation 2003; 107: rationale for such exclusion is based on such an approach can be advocated. 3133-40. little objective evidence of risk. Con- 17. WOLFE F, MICHAUD K: Heart failure in rheumatoid arthritis: rates, predictors, and the ef- cerns regarding autoimmune worsen- References fect of anti-tumor necrosis factor therapy. Am ing with the use of a TNF inhibitor 1. LOVINGER SP: Use of biologics in rheuma- J Med 2004; 116. stem from: 1) rare occurrences (less than toid arthritis tempered by concerns over safe- 18. LENNART I, JACOBSSON H, TURESSON C et 200 total cases amongst > 600,000 pa- ty, cost. JAMA 2003; 289: 3229-30. al.: Arthritis Rheum 2003; Suppl. [abstract 2. CUSH JJ: Cytokine inhibitors. In HOCHBERG 540]. tients treated worldwide) of lupus or MC, SILMAN AJ, SMOLEN JS, WEINBLATT 19. MCKAY J, RAU R, WEISMAN M, et al.: A dou- MS in those receiving TNF inhibitors; ME and WEISMAN MH (Eds.): Rheumatolo- ble-blind randomized, six-arm, parallel-

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