Best Practice & Research Clinical Rheumatology
`Vol. 20, No. 4, pp. 757e790, 2006
`doi:10.1016/j.berh.2006.06.002
`available online at http://www.sciencedirect.com
`
`10
`
`Problems encountered during anti-tumour
`necrosis factor therapy
`
`Sheetal B. Desai* MD
`Fellow in Rheumatology
`
`Daniel E. Furst MD
`Carl M. Pearson Professor of Rheumatology
`
`Department of Rheumatology, University of California, Los Angeles, CA, USA
`
`Worldwide, over 400 000 patients have been treated with tumour necrosis factor (TNF)-a
`antagonists for indications that include rheumatoid arthritis, juvenile rheumatoid arthritis, in-
`flammatory bowel disease, psoriatic arthritis and ankylosing spondylitis. Since their approval,
`concerns regarding safety have been raised. There is a risk of re-activation of granulomatous
`diseases, especially tuberculosis, and measures should be taken for detection and treatment
`of latent tuberculosis infections. Preliminary data suggest that anti-TNF therapy may be safe
`in chronic hepatitis C. However, TNF-a antagonists have resulted in re-activation of chronic
`hepatitis B if not given concurrently with antiviral therapy. Solid tumours do not appear to
`be increased with anti-TNF therapy. Variable rates of increased lymphoma risk have been
`described with anti-TNF therapy compared with the general population, although no in-
`creased risk was found compared with a rheumatoid arthritis population. Large phase II
`and III trials with TNF-a antagonists in advanced heart failure have shown trends towards
`a worse prognosis, and should therefore be avoided in this population. Both etanercept
`and infliximab are associated with the formation of autoantibodies, and these autoantibodies
`are rarely associated with any specific clinical syndrome. Rare cases of aplastic anaemia, pan-
`cytopenia, vasculitis and demyelination have been described with anti-TNF therapy. This
`chapter will discuss the safety profile and adverse events of the three commercially available
`TNF-a antagonists: etanercept, infliximab and adalimumab. The data presented in this review
`have been collected from published data,
`individual case reports or series, package inserts,
`
`* Corresponding author. Address: Department of Rheumatology, University of California, Los Angeles, 1000
`Veteran Avenue, Room 32e59, Los Angeles, CA 90095-1670, USA. Tel.: þ1 310 825 7992; Fax: þ1 310 206
`8476.
`E-mail address: sheetaldesai@gmail.com (S.B. Desai).
`1521-6942/$ - see front matter ª 2006 Elsevier Ltd. All rights reserved.
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`758 S. B. Desai and D. E. Furst
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`the Food and Drug Administration postmarketing adverse events surveillance system,
`and abstracts from the American College of Rheumatology and European Congress of Rheu-
`matology meetings for 2005.
`
`Key words: TNF alpha antagonists; TNF alpha Blocking agent; adverse events; toxicity.
`
`SAFETY OF TNF-a ANTAGONISTS AND INFECTIONS
`
`General infections
`
`Bacterial and viral infections following use of tumour necrosis factor (TNF) antagonists
`continue to be a source of concern. In this examination of such infections, several ca-
`veats have to be considered. Firstly, although preregistration studies can be used, post-
`marketing studies, which are longer, are examined more frequently. Unfortunately,
`postmarketing studies are not well controlled for selection bias and bias by indication,
`and follow-up is often not as close as in premarketing studies. Secondly, significant
`infections and serious infections are often poorly defined and definitions differ between
`studies. This section will review studies of
`infections in general separately from
`serious infections. The data reviewed comes from preregistration studies, retrospec-
`tive studies, observational studies, and registry data.
`
`Infections
`
`Data regarding infections in general come from epidemiological studies. The
`CORRONA database examined 5596 rheumatoid arthritis (RA) patients, followed
`for 6817 patient-years, and compared patients on TNF inhibitors (3012 patients
`over 2722 patient-years; 48% on infliximab, 40% on etanercept and 12% on adalimu-
`mab) with patients not using TNF inhibitors. Infections were physician estimated and
`no specific definitions were given. Thirty-seven infections occurred per 100 patient-
`years in the anti-TNF group, compared with 29 infections per 100 patient-years in
`patients not using TNF inhibitors. After adjusting for age, sex, disease duration, dis-
`ease activity, comorbid conditions, previous disease-modifying antirheumatic drugs
`(DMARDs) and prednisone, there was a small
`increase in these infections in
`patients using TNF inhibitors; the incident rate ratio was 1.16 [95% confidence
`interval (CI) 1.06e1.28, P ¼ 0.002].1 Data from the German Biologics Registry
`gave fairly similar results.2 Although fewer patients were included, the analysis in
`the German study was well conducted. A 1-year follow-up was performed and
`512 etanercept-treated patients, 346 infliximab-treated patients and 601 patients
`on DMARDs were examined. In this study, the definition of serious adverse events
`was similar to that used by the Food and Drug Administration (FDA) (i.e. requiring
`hospitalization, prolonging hospitalization, associated with death or felt to be po-
`tentially life-threatening), but the definition of a serious infection was not clear.
`Other infections were also studied, although their definitions were also unclear.
`Between 22.6% and 28.3% of patients on TNF blockers had some type of infection,
`compared with 6.8% of the DMARD controls. The controls had less severe disease
`than the anti-TNF-treated patients and, after propensity scoring was used for ad-
`justment, the authors pointed out that the relative risk for comparable patients
`should probably be decreased by approximately one-third. Thus, for all infections,
`the relative risk of 3.3e4.14 (95% CI > 1) was decreased to 2.13e2.16 (95%
`CI > 1) after adjusting for propensity scoring. This article pointed out
`that
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`pulmonary, skin, and herpes infections, in particular, occurred more frequently in
`patients using etanercept or infliximab, while infections of the gastrointestinal tract,
`bones and joints did not appear to be increased in these patients.
`
`Serious infections
`
`Of a total of seven studies, three indicated that serious infections occurred more fre-
`quently in association with TNF-blocking agents, and four studies showed no differ-
`ences compared with other DMARDs.
`Two retrospective reviews indicated some propensity for increased serious infec-
`tions among patients using TNF-blocking agents. Salliot et al examined 707 patients
`and compared infections occurring in the period before starting TNF-a inhibitors
`with infections occurring during TNF-a-blocker therapy.3 Among the 275 infections
`that were noted after anti-TNF therapy was initiated, 5% were serious (14 infections).
`Of the 14 serious infections, 10 were bacterial infections and four were either mycobac-
`terial or viral. The authors calculated that the serious infection rate was 2.9  35 per
`100 patient-years in the period prior to anti-TNF therapy, compared with 8.8  78
`per 100 patient-years during anti-TNF therapy (P ¼ 0.02). However, given the very
`high standard deviations, the inference that there was a difference cannot be drawn
`with any confidence. The second retrospective study examined 60 patients from a single
`centre and did not define serious infections.4 Eleven infections were reported; six in pa-
`tients using infliximab and five in patients using etanercept. Methotrexate and predni-
`sone were used by most patients. The infection rate before using TNF blockers was
`0.08 infections/year compared with 0.181 infections/year after starting TNF blockers.
`A retrospective analysis of clinical trials using adalimumab was carried out by Kent
`et al.5 In these phase I-III trials, with a long-term open-label extension in 2504 patients
`over 7591 patient-years, infections were defined primarily as those requiring hospital-
`ization. There were 257 serious infections. The serious infection rate was between
`0.042 and 0.049/patient-year. This was compared with historical DMARD controls
`of 0.03e0.10/patient-year, and was not found to be different. Without concomitant
`controls, these data need to be viewed with some scepticism. Another study had con-
`comitant controls.6 On a methotrexate background, patients were given adalimumab
`40 mg every other week, adalimumab 40 mg weekly, or placebo. There were approx-
`imately 200 patients/group. Although infections were not defined, the infection rate/
`year was 0.06 in the placebo group, 0.08 in the alternate-week adalimumab group
`and 0.18 in the weekly adalimumab group (no statistics were given but these do not
`appear to be markedly different in this 1-year study).
`The results of three studies of infections with TNF-a antagonists came from regis-
`tries. The UK nationwide registry compared patients on TNF-a antagonists (2247 eta-
`nercept patients, 2398 infliximab patients and 659 adalimumab patients) with 648
`patients on DMARDs.7 Serious infections were defined as those requiring hospitaliza-
`tion, intravenous antibiotics or resulting in death. After adjusting for age, sex, disease
`duration, disease severity (not defined), steroids, comorbidities and smoking, there
`were no differences between the serious infection rates in those using etanercept,
`infliximab or adalimumab compared with the DMARD controls (0.97 vs 0.98 vs 1.27,
`respectively; P ¼ not significant). The same conclusion was made by the Swedish
`Arthritis Treatment Group, which followed anti-TNF therapy in 412 RA patients
`between 1999 and 2001.8 These patients represented more than 90% of all RA patients
`given TNF blockers in eight hospitals in Sweden. Severe infections such as sepsis, septic
`arthritis, meningitis, peritonitis or death occurred in eight patients during 778 patient-
`years in patients using TNF blockers compared with 28 in 2538 patient-years in those
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`not using TNF blockers. A clear weakness in this study was that the RA patients on TNF
`blockers were from hospitals and the control patients were from the community. After
`adjusting for numerous other variables, including disease severity, steroids and other
`DMARDs, the relative risk ratio for these severe infections was between 0.89 and
`1.15 (not significant). The German Biologics Registry, mentioned previously, also exam-
`ined serious infections (see above for definition).2 In this case,
`in a registry that
`appeared to be somewhat larger than the other two registries, the relative risk ratio
`of serious infection was approximately 2.1.
`
`Summary
`
`There is some evidence that non-serious infections are increased slightly (relative risk
`of approximately 2) when patients use TNF blockers. While the data regarding serious
`infections are somewhat inconsistent, it is probable that there is no increase in these
`infections compared with RA patients using DMARDs.
`
`Tuberculosis
`
`In animal models, TNF-a plays an essential role in host defence against tuberculosis
`including granuloma formation and containment of disease.9e12 In a mouse
`(TB),
`model of latent TB, antibodies to TNF-a caused re-activation of TB, suggesting that
`TNF-a antagonists may increase susceptibility to TB.13 Although preregistration
`studies with TNF-a antagonists revealed 15 cases of TB among approximately 8000
`treated RA patients, passive surveillance studies have indicated a higher incidence
`of TB in association with TNF-a antagonists, and a possible higher incidence associ-
`ated with infliximab over etanercept.14 The data available to date are briefly reviewed
`below.
`There have been several reviews of the FDA’s Adverse Events Reporting System
`(AERS) examining reports of TB associated with TNF-a antagonists. Keane et al
`published the first review of the AERS database, conducted from 1998 to May
`2001.15 Seventy cases of TB were reported with infliximab, occurring at a median in-
`terval of 12 weeks after initiation of infliximab therapy. Forty of the 70 patients (56%)
`had extrapulmonary disease and 24% had disseminated disease. The estimated rate of
`TB among RA patients treated with infliximab in the USA was 24.4 cases/100 000/year,
`compared with a background rate of TB in patients with RA in the USA of 6.2 cases/
`100 000/year.16 Although no statistical parameters were provided, the authors sug-
`gested that there was a higher risk of TB in patients with RA treated with infliximab,
`that this risk was highest soon after initiation of treatment, and that the pattern of TB
`disease was unusual with a greater percentage of extrapulmonary and disseminated
`disease.15 Mohan et al reviewed the AERS database from November 1998 to March
`2002 and described 25 cases of TB occurring in association with etanercept, with a me-
`dian interval of 11.5 months.13 Thirteen of the 25 patients (52%) had extrapulmonary
`disease. The estimated reporting rate of TB in patients with RA treated with etaner-
`cept was approximately 10 per 100 000 patient-years of exposure, yet no statistical
`parameters were provided. The authors alerted clinicians of the unusual extrapulmo-
`nary presentations of TB that can be seen with etanercept. Wallis et al recently pub-
`lished a review of granulomatous infections with TNF-a antagonists that were
`reported to the AERS database from January 1998 to September 2002.17,18 TB was
`the most frequently reported disease, with 144 cases per 100 000 patients reported
`with infliximab and 35 per 100 000 patients reported with etanercept. The authors
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`concluded that the risk of granulomatous infection was 3.25-fold greater among pa-
`tients who received infliximab than in patients who received etanercept (no statistical
`analysis was given), and that the clustering of reports shortly after initiation of inflix-
`imab treatment likely represented re-activation of latent infection.
`Recently, Abbott Pharmaceuticals released data regarding adalimumab and the risk
`of TB.19,20 In global clinical trials with 10 050 patients with longstanding RA (defined as
`disease duration 3 years), all of whom were screened for latent TB before entering
`the trials, the event rate of TB per 100 patient-years was 0.24. For 542 patients with
`early RA (defined as disease duration <3 years), again prescreened for TB, the event
`rate of TB was 0.11 per 100 patient-years.19 In an analysis of the US postmarketing
`safety of adalimumab from Abbott-supported trials from 2002 to 2004, with pre-
`screened patients with an estimated 55 384 patient-years of exposure, 11 patients
`were reported to have TB, yielding a rate of 0.02 per 100 patient-years.20 Only three
`of the 11 (27%) patients had extrapulmonary TB.
`Several studies have been performed to evaluate the risk of TB in patients treated
`with TNF-a antagonists. Gomez-Reino et al analysed the BIOBADASER (Spanish
`Society of Rheumatology Database on Biologic Products) database established in
`February 2000 for patients with rheumatic diseases treated with biologic therapy.21
`As of February 2002, there were 17 reported cases of TB in the 1540 patients regis-
`tered, and all were associated with infliximab. Compared with a background rate of TB
`of 21 cases per 100 000 inhabitants in Spain in 2000, the relative risk ratio of TB in
`patients treated with infliximab compared with the general population was 90.1
`(95% CI 58.8e146.0). Compared with an RA cohort from a similar patient population
`not treated with anti-TNF therapy, where the incidence of TB was estimated to be 95
`cases per 100 000 patients, the estimated relative risk of TB in infliximab-treated pa-
`tients compared with RA patients not treated with TNF-a antagonists was 19.9 (95%
`CI 16.2e24.8) in 2000 and 11.7 (95% CI 9.5e14.6) in 2001. The authors concluded
`that therapy with infliximab was associated with an increased risk of TB compared
`with the general population and the RA controls. It should be remembered, however,
`that this data arose in an era when prescreening for TB was just beginning and it would
`be difficult to extrapolate the data to the present day.
`Two recent studies were performed in an era when prescreening for TB is standard
`of care. Thus, these studies are more appropriate for today’s practice. Wolfe et al pub-
`lished a study that evaluated the rate of TB in RA patients treated with anti-TNF ther-
`apy in the USA.16 The risk of TB in RA patients treated with infliximab and etanercept
`was evaluated and compared with 10 782 RA patients treated in the era prior to bi-
`ologics. Evaluating the 10 782 patients from June 1998 to December 1999 who
`were not treated with biologics, the baseline rate of TB was calculated to be 6.2 cases
`per 100 000 patients (95% CI 1.6e34.4). This was compared with the Centers for Dis-
`ease Control and Prevention’s reported rate of TB in the general US population of 6.4
`per 100 000 people in 1999 and 5.8 per 100 000 people in 2000. Thus, the authors
`concluded that the rate of TB in patients with RA compared with the general popu-
`lation was not increased. When they evaluated the patients treated with infliximab
`(6460 patients) and etanercept (2327 patients), a total of four cases of TB were re-
`ported, all occurring in the infliximab-treated group. Seventy-five percent of the TB
`cases were extrapulmonary and generally occurred shortly after infliximab treatment
`was started. The calculated rate of TB in RA patients treated with infliximab was 61.9
`cases per 100 000 patients; a figure much higher than the rate for the general popu-
`lation (5.8e6.4 per 100 000 people) and control RA group (6.2 cases per 100 000
`patients).
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`A recent study by Askling et al sought to determine the risk of TB in RA patients
`treated with TNF-a antagonists in Sweden.22 The risk of TB in the general population
`in Sweden was reported to be five cases per 100 000 people. Using data from nationwide
`and population-based registers, 15 cases of TB were reported in RA patients treated
`with anti-TNF therapy from 1999 to September 2004. Eleven cases were associated
`with infliximab and six cases were associated with etanercept (two patients received
`both agents). The mean duration of anti-TNF therapy was 10 months and 67% of patients
`had pulmonary TB. The calculated relative risk of TB in RA patients on anti-TNF therapy
`compared with a control RA group not treated with TNF-a antagonists was 4.0 (95% CI
`1.3e12). The calculated relative risk of TB in the control RA population compared with
`the general Swedish population was 2.0 (95% CI 1.2e3.4). The authors concluded that,
`irrespective of anti-TNF therapy, Swedish patients with RA are at increased risk for TB,
`and that treatment with TNF-a antagonists further increased this risk.
`Although passive surveillance data are often insufficient to prove a causal relation,
`all three reviews of the AERS database revealed an increased risk of TB and predom-
`inance of atypical TB presentations in anti-TNF-treated patients compared with the
`general population. However they suffer from not being performed when prescreening
`for TB was standard of care. They also revealed a generally higher incidence of TB with
`infliximab over etanercept, occurring at the greatest frequency within the first 12
`weeks after initiation of infliximab treatment. Furthermore three epidemiological stud-
`ies carried out in Spain, the USA and Sweden all corroborated these findings, although
`the relative rates of TB in these studies varied greatly. This suggests, but does not
`prove, that the risk of TB is different for infliximab and etanercept. Several theories
`have been proposed to explain why this risk is different, and include differences in
`the mechanism of action and neutralization of TNF-a by infliximab, the longer half-
`life of inliximab, greater use of infliximab in Europe where there is a higher background
`incidence of TB, and greater frequency of combination therapy of infliximab with other
`immunosuppressants such as methotrexate.23
`Screening for TB is strongly recommended prior to initiating therapy with TNF-a
`antagonists. Several consensus guidelines for screening and treatment have been
`proposed by different organizations in Spain, France and the USA.21,24,25 A study by
`Carmona et al in Spain is the first published study evaluating the effectiveness of rec-
`ommendations set forth to prevent re-activation of latent TB in patients treated with
`TNF-a antagonists.26 Data regarding TB associated with anti-TNF therapy were ex-
`tracted from the BIOBADASER registry. They found 34 cases of active TB, of which
`only two (5.8%) cases developed after the recommendations for TB screening were
`instituted. Rates of active TB after implementation of the recommendations decreased
`by 78% (incidence risk ratio 0.22, 95% CI 0.03e0.88, P ¼ 0.008), highlighting the effec-
`tiveness of their strategies.
`
`Summary
`
`Re-activation of TB is a concern with inhibition of TNF-a. However, it is difficult to
`have universal guidelines for TB screening in patients treated with TNF-a antagonists
`given the differences in the incidence and prevalence of TB in different populations,
`and the variations in customary practices from country to country. We suggest the
`following:
`
`1. All patients should be counselled thoroughly regarding the risks of TB prior to
`consideration of anti-TNF therapy.
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`2. All patients should be screened for latent TB with history, physical examination
`and purified protein derivative (PPD) skin tests. It is important to point out that
`RA patients’ PPDs may be affected by their underlying disease and/or the treat-
`ment of their RA, both tending to increase the possibility of false-negative skin tes-
`ts.27e32 Thus, it may be appropriate to consider chest films in RA patients where
`there is suspicion of a compromised skin test.
`latent TB (a positive PPD  positive chest radiography, without
`3. Treatment of
`evidence of active disease) should be initiated prior to starting anti-TNF therapy.
`There is a paucity of data in the literature regarding when TNF-a antagonists can
`be started, whether treatment with a single agent (i.e. isoniazide (INH)) is suffi-
`cient, and how long the therapy should be continued. Most authorities appear
`to use INH alone, but the duration of therapy before starting anti-TNF therapy
`has ranged from 1e2 weeks to 6 months. Likewise, the duration of INH therapy
`that is considered to be sufficient has ranged from 6 to 9 months, and the insis-
`tence on observed treatment (i.e. observing each time the tablets are taken) has
`been controversial.33
`4. Clinicians must be aware of the preponderance of unusual TB case presentations
`(extrapulmonary involvement and disseminated disease) in patients treated with
`TNF-a antagonists.
`5. TNF-a antagonists should be discontinued immediately in the setting of active TB
`infection. Whether or not to resume anti-TNF therapy after TB treatment is com-
`pleted is still controversial.
`
`Viral infections
`
`Hepatitis C
`
`Hepatitis C virus (HCV) infection is endemic in most areas of the world and is
`estimated to infect nearly 200 million people worldwide.34 There is a growing body
`of evidence demonstrating elevated levels of TNF-a in HCV patients compared with
`controls, and there is a correlation between elevated TNF-a levels and serum alanine
`aminotransferase (ALT) levels.35 These findings suggest that TNF-a may be involved in
`the pathogenesis of hepatocyte destruction in chronic HCV.
`At the time of this writing, there have been eight published reports of patients with
`HCV treated with etanercept or infliximab, one prospective analysis of eight patients
`with HCV treated with infliximab or etanercept, and one randomized controlled trial
`of 19 patients with HCV treated with etanercept.36e44 One of the case reports
`describes two patients treated with infliximab for hepatitis-C-associated mixed cryo-
`globulinaemia; however, no mention of the effect of infliximab on liver function tests or
`HCV viral load was made.43 The other seven case reports encompass a total of 29
`patients with chronic HCV [documented by presence of HCV antibodies, positive
`HCV ribonucleic acid (RNA) viral
`loads, and a range of normal to abnormal ALT
`and aspartate aminotransferase levels].36e42 These 29 patients with chronic HCV in-
`fection were treated with etanercept (17þ cases) or infliximab (7þ cases) for a variety
`of disease states such as RA (22 cases), Crohn’s disease (three cases) and psoriatic
`arthritis (four cases). The dose of etanercept used was 25 mg subcutaneously twice
`weekly in all cases, except for several case reports with psoriatic arthritis where
`the dose was titrated up to 50 mg subcutaneously twice weekly. The dose of infliximab
`used varied from 3 to 5 mg/kg, either given once or given at weeks 0, 2 and 6 and then
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`764 S. B. Desai and D. E. Furst
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`at 8-week intervals. All seven published case reports, which encompassed 29 patients
`with HCV treated with TNF-a antagonists, concluded that there were no flares of
`chronic HCV after initiation of treatment with infliximab or etanercept, as docu-
`mented by stable liver function tests and/or stable HCV viral load. To date, no cases
`of HCV treated with adalimumab have been reported.
`A published prospective analysis evaluated eight patients with RA and chronic
`HCV who were treated with etanercept 25 mg subcutaneously twice weekly.42
`The patients were followed for 4 months, and there were no statistically significant
`changes in serum aminotransferases or mean viral load. Interestingly, the viral load
`decreased in seven of the eight patients while taking etanercept, but the difference
`did not achieve statistical significance. A phase II randomized, double-blind, placebo-
`controlled study was reported recently, evaluating etanercept for the treatment of
`chronic HCV.44 Fifty patients with chronic HCV were randomized to receive inter-
`feron, ribavirin and placebo or interferon, ribavirin and etanercept (25 mg subcuta-
`neously twice weekly). The author found a higher frequency of disappearance of
`HCV RNA at 24 weeks in the etanercept group (63%) compared with the placebo
`group (32%) (P ¼ 0.04). In addition, more patients in the etanercept arm had ALT
`normalization and no detectable HCV RNA at 24 weeks when compared to placebo
`(58% with etanercept vs 28% with placebo, P ¼ 0.04).
`
`Summary. Case reports, a small prospective study and a randomized, double-blind,
`placebo-controlled study all indicate that anti-TNF therapy may be safe, and even ben-
`eficial, to use in chronic HCV. These data are very preliminary, and one must continue
`to exercise great caution when considering the use of anti-TNF therapy in chronic
`HCV infection. Interval monitoring of serum aminotransferases and HCV viral load
`are recommended during therapy with TNF-a antagonists.
`
`Hepatitis B
`
`Hepatitis B virus (HBV) infection is the most common form of chronic viral infection,
`with an estimated burden of 350 million people worldwide.45 Elevated levels of TNF-
`a are seen in both the serum and hepatocytes of patients with chronic HBV, and are
`secreted by HBV-specific cytotoxic T lymphocytes (CTL).46,47 Animal studies show
`that TNF-a knockout mice have defects in the proliferative capacity of the HBV-
`specific CTL, suggesting that TNF-a may play a role in clearing or controlling
`HBV.48 Therefore, immunosuppression in chronic HBV could theoretically re-activate
`[conversion of undetectable to detectable HBV deoxyribonucleic acid (DNA) and
`elevated serum aminotransferases] or worsen the disease.
`To date, there are 11 reported cases of patients with chronic HBV infection
`(defined as persistence of hepatitis B surface antigen for more than 6 months  ele-
`vated aminotransferases  positive serum HBV DNA levels) treated with inflixi-
`mab.37,49e58 These case reports represent cases of chronic HBV with the following
`disease states: Crohn’s disease (five cases); RA (three cases); ankylosing spondylitis
`(two cases); and adult-onset Still’s disease (one case). The doses of infliximab used
`in these case reports varied from a single dose to multiple doses of 3e6 mg/kg. In
`only one of the 11 case reports did treatment with infliximab in a patient with RA,
`renal amyloidosis and chronic HBV result in disappearance of serum HBV DNA
`levels.49 In two case reports, concurrent use of infliximab with methotrexate resulted
`in re-activation of chronic HBV infection, documented by an elevation of baseline
`serum aminotransferase levels and an increase in serum HBV viral DNA levels (which
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`were either stable or previously undetectable).50,51 In one of these cases, discontinu-
`ation of infliximab and methotrexate and the addition of the antiviral agent lamivudine
`resulted in normalization of liver transaminases and a return to an undetectable HBV
`DNA level.50 In the other case, infliximab and methotrexate were continued while
`lamivudine was added, also resulting in normalization of liver transaminases and return
`to an undetectable HBV DNA level.51
`The patient with adult-onset Still’s disease and chronic HBV was treated with meth-
`otrexate and infliximab, but developed acute fulminant hepatitis 10 days after the sec-
`ond infliximab infusion and required a liver transplantation.52 The fulminant hepatitis
`was thought to be a drug reaction because the HBV DNA levels had remained negative
`and liver biopsy was negative for HBV. There are three case reports of the use of
`infliximab, without methotrexate, resulting in re-activation of chronic HBV infec-
`tion.53,54 In the remaining four case reports of anti-TNF therapy in HBV, infliximab
`was used concurrently with lamivudine, resulting in stable disease with no HBV re-
`activation.37,54e56 At the time of this writing, no cases of HBV re-activation with either
`etanercept or adalimumab have been reported.
`
`Summary. TNF-a promotes viral clearance in hepatitis B infection (at least in animals);
`this is different than its role in hepatitis C where it is postulated to promote chronic
`liver injury. The published case reports indicate that infliximab  methotrexate
`infliximab 
`re-activates chronic HBV infection, yet concurrent
`treatment of
`methotrexate with lamivudine can stabilize HBV disease activity. To date, there are
`no consensus guidelines regarding screening or treatment strategies for prevention
`of HBV re-activation in patients receiving anti-TNF therapy.
`Given the lack of prospective studies and randomized controlled trials with the use
`of TNF-a antagonists in HBV, we recommend screening all patients for hepatitis B
`prior to treatment with anti-TNF therapy by measuring a hepatitis B surface antigen,
`hepatitis B surface antibody and hepatitis B core antibody. For patients with chronic
`hepatitis B (a positive hepatitis B surface antigen for more than 6 months  elevated
`aminotransferases  positive serum HBV DNA levels), one should consider using anti-
`TNF therapy only in concert with hepatitis B treatment with antiviral agents such as
`lamivudine. These patients should be followed with periodic serum aminotransferases
`and serum HBV DNA levels. Studies are clearly needed to determine the safety of
`TNF-a antagonists in HBV infection and whether there are any long-term side effects
`of concomitant therapy with TNF-a antagonists and antiviral treatment.
`
`HIV
`
`Many rheumatic conditions can be seen with HIV infection, such as inflammatory
`arthritis, reactive arthritis, psoriasis, myositis and vasculitis.57 Historically, treatment
`of these inflammatory conditions has been difficult because patients with HIV are im-
`munocompromised as a result of their disease state. However today, with the use of
`highly active antiretroviral therapy (HAART), viral replication can be controlled and
`immune reconstitution can be induced. Thus, HIV patients stabilized on HAART
`may be capable of tolerating some degree of immunosuppression.
`Elevated TNF-a levels are seen throughout all stages of HIV infection, and TNF-a
`may contribute to increased CD4 cell apoptosis.58,59 To date, three controlled trials
`and three case reports of anti-TNF therapy in patients with underlying HIV infection
`have been published.60e65 The anti-TNF therapy used in these studies was either
`
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`766 S. B. Desai and D. E. Furst
`
`etanercept or infliximab, and no reports were found regarding adalimumab treatment
`in HIV patients.
`Walker et al assessed the safety of anti-TNF therapy in