Version July 2025
INTRODUCTION —
Targeted inhibitors of tumor necrosis factor-alpha (TNF-alpha) are widely used in the treatment of a number of inflammatory conditions, including inflammatory arthritis, inflammatory bowel disease (IBD), psoriasis, and sarcoidosis. However, prolonged use of these agents has been associated in some patients with the development of anti-drug antibodies (ADA), which may promote adverse effects and diminish drug efficacy and cost-effectiveness. Induction of autoimmunity, including both autoantibodies and, much less often, clinically evident autoimmune disease, may also occur during treatment with TNF-alpha inhibitors. These risks must be weighed, together with the risk of other adverse effects, against the potential benefits of therapy when deciding whether to use one of these agents in an individual patient.
This topic covers the formation of ADA and autoantibodies, as well as the development of autoimmune diseases, in the setting of TNF-alpha inhibitor use. Other major complications of anti-TNF therapy, including an overview of adverse effects, injection site and infusion reactions, infectious complications, and a potential risk of malignancy are described separately:
●(See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)
●(See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)
●(See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors".)
●(See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy".)
ANTI-DRUG ANTIBODIES —
The formation of anti-drug antibodies (ADA), especially drug-neutralizing ADA, is a concern with biologic tumor necrosis factor (TNF) inhibitors, particularly the monoclonal antibody agents infliximab, adalimumab, and golimumab, and biosimilars to these original drugs. ADA may cause allergic reactions, loss of drug efficacy, and increased cost of therapy. The risk of developing ADA appears least common with use of etanercept, a TNF receptor fusion protein, and most common with infliximab, a chimeric (mouse/human) antibody construct, and adalimumab, a humanized monoclonal antibody.
Common types of anti-drug antibodies — The composition and association with ADA induction of each of the four groups of biologic TNF inhibitors that are widely available for the treatment of autoimmune and inflammatory illnesses are:
●Chimeric mouse/human anti-TNF antibodies
•Infliximab and biosimilars to infliximab – The development of ADA is a significant concern with the use of infliximab and related biosimilars. They are most often neutralizing and are frequently associated with diminished or absent drug trough levels and response failure [1-9]. Infliximab and biosimilar drugs are composed of the human constant region of immunoglobulin G1 (IgG1) coupled to the variable regions of a mouse anti-TNF-alpha monoclonal antibody [10]. The associated ADA are predominantly directed against the mouse portions of the infliximab molecule and are thus sometimes referred to as human antichimeric antibodies (HACA). (See 'Infliximab-induced human antichimeric antibodies' below.)
●Human or humanized anti-TNF antibodies
•Adalimumab and biosimilars to adalimumab – Neutralizing anti-adalimumab ADA pose similar problems to those seen with infliximab, including lower or absent circulating levels of the drug and reduced clinical responsiveness, despite adalimumab being a humanized antibody [7,8,11-14]. Adalimumab is composed of a whole human IgG1 kappa monoclonal antibody specific for human TNF-alpha, thus selectively neutralizing TNF-alpha activity [10]. The drug binds to both the soluble and transmembrane bioactive forms of human TNF-alpha. The antibodies against adalimumab and biosimilars (called anti-adalimumab antibodies [AAA]) are most likely directed against idiotopes in the TNF-binding sites of the drugs. (See 'Adalimumab-induced human anti-human antibodies' below.)
•Golimumab – ADA have also been described in patients receiving golimumab [11,15], a fully human IgG1 kappa monoclonal antibody specific for human TNF-alpha that selectively neutralizes TNF-alpha activity [10]. Adverse clinical consequences of such antibodies, including reduced efficacy, are well described [8,16]. Like infliximab and adalimumab, golimumab binds to both the soluble and transmembrane bioactive forms of human TNF-alpha.
●Humanized anti-TNF Fab' fragment
•Certolizumab pegol – ADA can also develop against certolizumab pegol [8,11,17]. Certolizumab pegol is a chimeric (mouse/human) anti-TNF Fab' (Fc-free) antibody construct, which consists of the TNF-alpha-binding complementarity-determining region of a monoclonal mouse antibody inserted into a human Fab' IgG framework [10]. Polyethylene glycol is incorporated into the construct, as this may reduce antigenicity and also prolong the circulating half-life of the drug. In one clinical trial including 595 patients with Crohn disease, anti-certolizumab pegol ADA developed in 134 (23 percent) [17]. In 77 percent of the anti-certolizumab pegol-positives, the ADA were persistent and associated with reduced circulating levels of the drug and increased blood levels of C-reactive protein and fecal calprotectin indicating increased disease activity. There are fewer reports of ADA against certolizumab pegol compared with infliximab and adalimumab, and the clinical impact of ADA to this drug is not yet well defined.
●TNF-receptor fusion protein
•Etanercept and biosimilars to etanercept – ADA have also been described in patients treated with etanercept, although these are generally non-neutralizing and not associated with decreased trough drug levels, impaired clinical response, or adverse events [11,18]. Etanercept is a fusion protein consisting of two human p75 TNF-alpha receptors coupled to the constant region of human IgG1 [10]. It binds to and neutralizes both TNF-alpha and TNF-beta. While initial assessments of etanercept immunogenicity were unclear due to methodologic problems in the detection and measurement of anti-etanercept ADA, subsequent studies showed that ADAs for etanercept are lower and less neutralizing than those against other TNF inhibitors [18,19].
Biosimilar drugs with pharmacologic, structural, biologic, and therapeutic characteristics that closely match the initially marketed innovator molecules are widely used [20-23]; their ADA immunogenicity profiles are similar to those of the original molecules [8,24-26]. While data are limited, presumably ADA to an original molecule would also interfere with a related biosimilar drug and vice versa.
ADA induced by and directed against infliximab and adalimumab appear to be specific to each of these molecules. Cross-reactions with other chimeric monoclonal antibodies such as rituximab have been very rare in our experience.
Clinical effects — The adverse effects of ADA, including increased risk of hypersensitivity reactions, diminished efficacy, and reduced cost-effectiveness, have been documented in randomized trials and multiple observational studies [4,8]. Suspicion of ADA development should arise with clinical signs of hypersensitivity reactions and reduced drug efficacy, the latter preferably before intensifying drug delivery as this may increase the risk of side effects and prove to have no or only temporary effect. In drug-naïve patients, serum ADA are often detectable within two to six months of starting therapy. A 2017 systematic review of such evidence, which included data from patients treated with infliximab and the biosimilar CT-P13, adalimumab, golimumab, and etanercept, found the following [8]:
●Rates of ADA formation were generally higher in patients treated with chimeric anti-TNF constructs (infliximab and biosimilar to infliximab) compared with fully human monoclonal antibodies (golimumab) and the fusion protein etanercept. It is noteworthy that ADA against golimumab seem less likely to occur than ADA against adalimumab, which is developed by phage substitution, possibly making the antigen-binding epitopes immunogenic.
●Patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis with and without arthritis, juvenile idiopathic arthritis (JIA), Crohn disease, and ulcerative colitis treated with anti-TNF antibody constructs who developed ADA against the drug had lower serum drug levels than ADA-negative patients and were less likely to achieve a significant clinical response at six months and between months 6 and 12.
●Discontinuation of the biologic agent in patients with RA and/or axial spondyloarthritis with ADA was significantly more likely compared with patients without ADA.
●Hypersensitivity reactions among patients with all conditions were more common in ADA-positive patients and most prominent in those treated with infliximab and a biosimilar to infliximab.
●Cotherapy with a traditional "nonbiologic" disease-modifying antirheumatic drug (DMARD), methotrexate, azathioprine, leflunomide, or mycophenolate, was associated with decreased measurable levels of circulating ADA. There was no evidence in the literature of any differences between these DMARDs.
Infliximab-induced human antichimeric antibodies — The development of ADA against infliximab is associated with an increased risk of infusion reactions and a reduced response and duration of response to treatment [1,2,12]. Such ADA have been described in patients with RA, inflammatory bowel disease (IBD), and other disorders [1-3,6,7,12,22,27-30].
ADA directed against infliximab develop in approximately half of the patients treated with infliximab alone, ie, without other immunosuppressive or antiinflammatory drug therapies. This proportion is reduced by coadministration of methotrexate and other immunoinflammatory modulators [1,28,31,32]. For these reasons, infliximab was approved for use in RA in the United States and Europe together with methotrexate. However, such restrictions do not apply to the labeling approved for AS, IBD, and psoriasis, where clinical trials of the effect of methotrexate cotherapy on drug immunogenicity differ considerably. An immunosuppressive action of methotrexate on anti-infliximab ADA development has been proposed, but studies have been limited to measurement of ADA in the circulation and not the ability of methotrexate to interfere with the production of anti-infliximab ADA [33].
Examples of the effects of these antibodies in specific conditions include:
●IBD (Crohn disease and ulcerative colitis) – ADA were common in a cohort of 125 consecutive patients with Crohn disease treated with infliximab (mean of 3.9 infusions [range 1 to 17] over a mean of 10 months) and were associated with an increased risk of infusion reactions and a shorter duration of drug responsiveness [27]. The following observations were made:
•Anti-infliximab ADA were detected in 61 percent of patients. The presence of ADA concentrations of 8 mcg/mL or greater before an infusion predicted a shorter mean duration of response compared with patients with lower concentrations (35 versus 71 days).
•Higher ADA concentrations (8 mcg/mL or greater) before infusions were associated with a greater risk of an infusion reaction (relative risk 2.4, 95% CI 1.7-3.7), and infliximab concentrations were significantly lower at four weeks among patients who had had an infusion reaction than among patients who had never had an infusion reaction (median 1.2 versus 14.1 mcg/mL). Patients who had infusion reactions had a shorter median duration of clinical response (39 versus 65 days).
•The use of concomitant immunosuppressive/antiinflammatory therapy (azathioprine, mercaptopurine, methotrexate, or mesalamine) predicted lower measurable titers of circulating ADA against infliximab and higher concentrations of infliximab four weeks after an infusion.
●RA – ADA and a reduction in the duration of the response, which are similar findings to those seen in Crohn disease, have been reported in studies of patients with RA [1,6,12,28]. In one study, although low-dose methotrexate administration (7.5 mg/week) appeared to have little effect on the peak clinical response, it prolonged the duration of responses in most patients [28]. In addition, the incidence of ADA positivity correlated inversely with the dose of infliximab (53 versus 21 versus 7 percent of patients who received 1, 3, and 10 mg/kg, respectively). Concomitant methotrexate reduced the frequency of measurable ADA responses to 15, 7, and 0 percent, respectively, in those three treatment groups.
●Axial spondyloarthritis – One study examined the presence and impact of ADA to infliximab in 60 patients with radiographic axial spondyloarthritis over a period of 102 weeks [34]. ADA were found in almost half of the group (27 patients), typically within the first year of treatment, and were associated with lower rates of concomitant methotrexate use. Compared with patients without ADA, those with ADA had reduced survival for both the overall use of infliximab and tapering infliximab.
More than half of patients with RA receiving infliximab undergo increases in their regular dose over time or shortening of the interval at which the medication is administered [29,30]. In most cases, this "dose creep" correlates with the formation of ADA, but loss of efficacy may also result from the inflammatory disease process no longer being driven by TNF [19]. An alternative explanation for the need to increase infliximab doses over time might be underdosing at the start of therapy. Thus, some patients with RA or Crohn disease benefit from infliximab given at doses higher than the recommended 3 mg/kg or more frequently than every eight weeks [30]. These formerly clinical judgements can now be informed by measuring trough drug and ADA levels. (See 'Therapeutic drug monitoring' below.)
Adalimumab-induced human anti-human antibodies — ADA that develop in patients being treated with adalimumab are associated with lower serum adalimumab concentrations and reduced efficacy of adalimumab, with those receiving adalimumab monotherapy more likely to develop ADA compared with those taking methotrexate [12,35,36]. As an example, the frequency, concentration, and clinical impact of anti-adalimumab ADA were evaluated in 272 consecutive patients with RA begun on adalimumab and followed for three years. The following findings were reported:
●Anti-adalimumab ADA were detected in 76 patients (28 percent) during 156 weeks of treatment. Antibodies were detected within 28 weeks of beginning therapy in 67 percent of patients who became ADA-positive.
●Patients with moderate to high levels of ADA exhibited significantly lower adalimumab levels compared with patients without measurable ADA.
●These patients were also significantly less likely to achieve minimal disease activity (Disease Activity Score in 28 Joints [DAS28] <3.2) compared with patients without ADA (6 and 18 versus 48 percent). Additionally, patients with ADA were significantly more likely than those without such antibodies to discontinue study participation due to treatment failure (38 versus 14 percent).
●Patients with anti-adalimumab ADA were significantly less likely than those without such antibodies to have also received concomitant therapy with methotrexate (54 versus 82 percent).
Similar results were found in a cohort study of 340 patients with several types of inflammatory arthritis (RA, psoriatic arthritis, and axial spondyloarthritis). Patients on concomitant methotrexate had higher adalimumab levels compared with patients who were not taking methotrexate (8.4 mg/L versus 5.8 mg/L) and a lower likelihood of forming ADA (5 percent [5 of 108] versus 22 percent [13 of 58]) [36]. By contrast, the data are less clear in patients with IBD, where an analysis of six randomized trials that examined efficacy, pharmacokinetics, and safety of combination immunomodulator/adalimumab therapies failed to show any superior efficacy of combination therapy [14].
THERAPEUTIC DRUG MONITORING —
Some have advocated routinely assessing circulating drug and anti-drug antibody (ADA) levels for some tumor necrosis factor (TNF) inhibitors to better titrate therapy, an approach known as therapeutic drug monitoring (TDM). TDM is used for many nonbiologic medicines and can be proactive, where regular measurement of serum drug and ADA levels facilitates titration of therapy to a therapeutic range. Alternatively, TDM may be reactive, where serum drug and ADA levels are measured in the setting of poor therapeutic response or decreasing clinical efficacy; results can indicate if patients may benefit from adjusting the dose or frequency of therapy or switching to alternative therapy. TDM in the clinical setting has been proposed by some experts as a means to avoid unnecessary medical costs and improve the efficacy and safety of therapy [5,19,27,37,38].
Assays for ADA have continuously developed, and these tests are now widely available for clinical use. There is still variability between tests and a lack of agreed standard terminology in reporting results [36]. Further research is needed given the complex nature of ADA detection in the presence of free drug, uncertainty about the meaning of ADA results, and the inability of most assays to determine the in vivo function of ADA (eg, the neutralization capacity of ADA in individual patients). However, the availability of ADA and drug level tests and determination of therapeutically relevant trough drug levels for many TNF inhibitors can help guide rational decisions for optimal therapy [33,39-42].
The utility of TDM may vary based on the type of TNF inhibitor, phase of therapy (ie, induction versus maintenance), and underlying condition. As an example, clinical practice guidelines issued in 2024 for patients with inflammatory bowel disease (IBD), inflammatory arthritis, or psoriasis advocate for checking ADA for infliximab maintenance therapy but not for infliximab induction therapy or the induction or maintenance of other TNF inhibitors [43]. The potential role of TDM is addressed in more detail in disease-specific treatment topics. (See "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors", section on 'Therapeutic drug monitoring'.)
Multiple meta-analyses of TDM in different diseases suggest that it may provide benefit in certain scenarios [5,19,27,37,38]. One such meta-analysis from 2024 included over 2300 patients with IBD, inflammatory arthritis, or psoriasis who were starting infliximab (two studies), maintaining infliximab (four studies), maintaining adalimumab (three studies), or maintaining infliximab, adalimumab, or etanercept (one study) [38]. For patients maintaining infliximab, the likelihood of experiencing sustained disease control or remission was higher for the group undergoing TDM compared with the group without TDM (absolute risk difference of 146 more per 1000 patients treated for one year [95% CI 78-224]). By contrast, outcomes were similar for patients who did or did not have TDM while initiating infliximab or maintaining the other TNF inhibitors. In another 2024 meta-analysis of 24 studies where TNF inhibitors (mostly infliximab) were used to treat immune-mediated inflammatory diseases, TDM seemed especially beneficial for those with IBD [44]; specifically, patients undergoing proactive TDM had higher rates of clinical remission (relative risk [RR] 1.15, 95% CI 1.04-1.28) and lower rates of ADA development (RR 0.34, 95% CI 0.19-0.60), IBD-related surgery (RR 0.46, 95% CI 0.26-0.81), hospitalization (RR 0.60, 95% CI 0.43-0.83), and serious adverse events (RR 0.23, 95% CI 0.07-0.76) compared with patients who did not have TDM. In addition, patients with IBD undergoing reactive TDM had lower hospitalization rates and potential cost savings compared with those without reactive TDM. The analysis of TDM in patients with rheumatic diseases found limited evidence and therefore inconclusive benefits.
AUTOIMMUNITY
Autoantibodies — Many tumor necrosis factor (TNF) inhibitors have been associated with an increased risk of developing autoantibodies, including antinuclear antibodies (ANA), which are the most common; anti-double-stranded DNA (anti-dsDNA) antibodies (see 'Systemic lupus erythematosus' below); and antiphospholipid antibodies [32]. The incidence of each varies widely in clinical studies, depending in part on the disease being treated, the drug used, and coadministration of other immune-modulating therapies [32,44-46]. In patients with rheumatoid arthritis (RA), the presence of ANA appears to be a risk factor for the appearance of of anti-drug antibodies (ADA) against infliximab and adalimumab [47].
As examples [32]:
●Infliximab use in clinical trials was associated with the development of ANA and anti-dsDNA in 29 to 77 and 10 to 29 percent of patients, respectively.
●Etanercept treatment of RA patients was associated with ANA and anti-dsDNA antibodies in 11 to 36 and 5 to 15 percent, respectively.
●Adalimumab treatment in RA patients was associated with the development of ANA and dsDNA antibodies in 13 and 5 percent, respectively.
●Anticardiolipin and antinucleosome antibodies have also been reported in a few RA patients treated with TNF inhibitors, but have only been anecdotally associated with clinical manifestations. Anticardiolipin antibodies were very infrequent (<5 percent) [44]; antinucleosome antibodies developed more frequently with therapy (7 to 26 percent) and were often associated with ANA positivity [46].
Autoimmune diseases — Some patients treated with the biologic TNF inhibitors develop a clinically evident autoimmune condition, presumably as a result of therapy; however, this occurs only in a small fraction of patients despite the substantial frequency of autoantibodies in patients receiving these drugs [48,49]. The majority of cases of autoimmune disease reported among patients receiving TNF inhibitors have been vasculitic syndromes, most often cutaneous vasculitis; lupus-like syndromes; or psoriatic skin changes. In most of these patients, the condition resolves with discontinuation of the offending drug and use of medications of a different class, but some patients require therapy specifically targeting the complicating autoimmune manifestations [48-51]. It appears that conventional disease-modifying antirheumatic drugs (DMARDs) may lower the risk of infusion reactions and lupus- and vasculitis-like events [52].
Systemic autoimmune conditions associated with TNF inhibitor use include:
●Drug-induced lupus syndromes (see 'Systemic lupus erythematosus' below)
●Systemic vasculitis (see 'Vasculitis' below)
●Sarcoidosis (see "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Pulmonary disease')
●Antiphospholipid syndrome [48]
●Dermatomyositis (DM)/polymyositis (PM) [53]
Organ-specific autoimmune disorders include:
●Cutaneous vasculitis (see 'Vasculitis' below)
●Psoriatic skin lesions and other cutaneous reactions (see "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Psoriatic skin lesions' and "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Cutaneous reactions')
●Uveitis and other inflammatory eye disease, including optic neuritis (see 'Other conditions' below)
●Interstitial lung disease (ILD) (see 'Other conditions' below)
●Demyelinating disease, including multiple sclerosis (MS) and MS-like disease, optic neuritis, and peripheral neuropathies (both demyelinating and others [49,54]) (see "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Demyelinating disease')
●Autoimmune hepatitis [49,54,55]
Several lines of evidence support the view that TNF inhibitor use is causally linked to these syndromes, particularly vasculitis [48,56], including:
●The temporal association between the use of TNF inhibitor therapy and the development of clinical features of an autoimmune disease
●The resolution of the autoimmune condition following the cessation of targeted TNF treatment
●The original appearance in some cases of leukocytoclastic vasculitis at the site of etanercept injections
●The reappearance or worsening of the symptoms upon re-exposure to the TNF inhibitor in a majority of cases in which rechallenge has been attempted [56]
Vasculitis — Most cases of vasculitis are confined to the skin and demonstrate findings of a leukocytoclastic vasculitis, although a minority of patients with vasculitis have systemic involvement, usually of the peripheral nerves or kidney [48].
In a series that analyzed all 233 cases of autoimmune disease induced by TNF inhibitors and reported in the medical literature through December 2006, 113 cases of vasculitis were described [56]. Ninety-eight (87 percent) of the patients with vasculitis had cutaneous involvement. Among these, the following lesions were observed:
●Palpable purpura – 55 patients (57 percent)
●Erythematous papules/macules/punctate lesions – 11 (11 percent)
●Ulcers – 9 (9 percent)
●Nodules – 9 (9 percent)
In terms of visceral involvement by vasculitis, the peripheral nerves and kidneys were affected in 18 (16 percent) and 15 (13 percent) patients, respectively.
Eighty-three (73 percent) of the 113 vasculitis cases were confirmed histopathologically. Among these, leukocytoclastic vasculitis was reported in 52 patients (63 percent), necrotizing vasculitis in 14 (17 percent), lymphocytic vasculitis in 5 (6 percent), and other findings in 12 (14 percent).
Ninety-two percent of the cases of vasculitis resolved following the discontinuation of TNF inhibitors. Vasculitis recurred in 12 of 16 (75 percent) patients rechallenged with a TNF inhibitor.
Systemic lupus erythematosus — Most cases of drug-induced lupus associated with the use of a biologic TNF inhibitor are characterized by mucocutaneous features, arthralgia or polyarthritis, and pleuropericardial abnormalities, along with the formation of autoantibodies such as those to dsDNA, the Sm antigen, or histones [56-66]. Kidney and neurologic manifestations are extremely rare, and the nature of their association with use of a TNF inhibitor remains uncertain [60]. Estimates of the frequency with which patients satisfy classification criteria for systemic lupus erythematosus (SLE) range from 28 to 64 percent [56,63,66]. The syndrome generally resolves after drug discontinuation, although many of the reported patients have also received glucocorticoid therapy. (See "Drug-induced lupus", section on 'Causative drugs'.)
In a representative series that analyzed all 233 cases of autoimmune disease induced by TNF inhibitors reported in the medical literature through December 2006, 92 cases of SLE or lupus-like illness were described (39 percent) [56]. Among the 72 patients in whom sufficient information was available to determine the frequency of the 1997 updated American College of Rheumatology (ACR) criteria for SLE [67], only 37 (51 percent) met the required threshold of fulfilling four or more criteria. This figure was just 35 percent if features already present before TNF inhibitors were started were excluded from consideration.
The frequencies of the following features were observed:
●ANA – 79 percent
●Anti-dsDNA antibodies – 72 percent
●Cutaneous features – 67 percent
●Arthritis – 31 percent
In this series and others, serositis was less common than rash or arthritis, and kidney and neurologic manifestations were rare [61,62]. The frequency of anti-histone antibodies, a hallmark of drug-induced lupus caused by procainamide or hydralazine, ranged from only 17 to 57 percent [57,61].
The rarity of drug-induced lupus due to TNF inhibitors was illustrated in observations from a large French registry, in which the incidence among patients treated with infliximab or etanercept was approximately 0.2 percent, with too few data for adalimumab to make an accurate estimate [57], although lupus-like syndromes have been reported in some adalimumab-treated patients [56,58].
In one of the largest series, the symptoms and signs of SLE resolved following the discontinuation of the TNF inhibitor in 71 of the 72 patients in whom information regarding disease outcome was available [56]. Resolution of SLE was seen in other series as well, although many of the patients also received glucocorticoids for the related symptoms [61]. The use of concomitant methotrexate, which is thought to reduce the frequency of autoantibodies when using anti-TNF agents, did not appear to protect against the development of TNF inhibitor-induced SLE or lupus-like illness. A review of literature that validated cases of SLE associated with TNF-inhibitor use against formal classification criteria for SLE has similar overall conclusions [68].
Other conditions — Additional conditions with autoimmune features have been described (see 'Autoimmune diseases' above):
●Interstitial lung disease – Pulmonary disease, particularly ILD, has been reported in at least 119 patients in association with use of a TNF inhibitor [69,70]. However, the relationship between TNF inhibitor use and the development of ILD is less clear than the association with cutaneous vasculitis or lupus-related syndromes. In most cases in which the lung disease has taken an aggressive course, the patients have had underlying disorders such as RA that place them at risk for ILD, making it impossible to exclude confounding by indication as a factor in these reports. In a 2011 literature review, the prognosis in patients with TNF inhibitor-related ILD was poor in patients in whom outcomes were reported, with an overall mortality rate of approximately one-third, and a mortality rate of two-thirds in those with pre-existing ILD exacerbated by use of the drugs [70]. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Pulmonary disease' and "Drug-induced lung disease in rheumatoid arthritis", section on 'Biological agents'.)
●Uveitis – Ocular inflammation of the uveal tract (uveitis) has been reported in association with the use of anti-TNF agents. It is most common in patients with ankylosing spondylitis (AS) [71]. Notably, the TNF inhibitors are also used to treat uveitis of multiple etiologies. (See "Uveitis: Treatment", section on 'Tumor necrosis factor-alpha inhibitors'.)
One registry-based study that included spontaneous reports of uveitis during the period from January 1, 1998 through January 1, 2006 noted 43 cases in patients who were receiving anti-TNF therapy [72]. After exclusion of patients with diseases associated with an increased risk of uveitis (eg, AS, Crohn disease, or juvenile idiopathic arthritis [JIA]), the numbers of patients taking etanercept, infliximab, or adalimumab in the remaining cases were 20, 4, and 2, respectively. The authors of this study concluded that, although the risk of uveitis was greater, this should not influence the initial choice of anti-TNF agent, but they did suggest that, for a patient without an underlying disease known to predispose to uveitis who develops uveal inflammation during treatment with etanercept, a switch to an anti-TNF antibody (infliximab or adalimumab) would be an option to consider. Other evidence suggests a preference for the use of monoclonal anti-TNF agents, such as infliximab or adalimumab, rather than etanercept, in patients with AS with an active or previous history of uveitis [50,73]. (See "Uveitis: Treatment", section on 'Tumor necrosis factor-alpha inhibitors'.)
●Inflammatory myopathy – At least 20 patients have been described with new onset of DM or PM during treatment with TNF inhibitor therapy, most of whom were being treated for RA [53]. Six of the patients exhibited antisynthetase antibodies, most were ANA-positive, and some patients had ILD. Improvement of the DM/PM was reported in most patients with withdrawal of the presumed offending agent and treatment with other immune suppressive therapies.
SUMMARY
●Anti-drug antibodies (ADA) – The risk of forming neutralizing ADA, which may result in diminished drug efficacy and increased risk of adverse reactions, varies with the specific type of tumor necrosis factor (TNF) inhibitor. ADA are most commonly observed with use of infliximab, adalimumab, and their respective biosimilars. Neutralizing ADA occur rarely with etanercept. Most commonly used assays do not reveal whether or not reported ADA are neutralizing in vivo. (See 'Common types of anti-drug antibodies' above.)
•Clinical effects – ADA formed in response to infliximab, adalimumab, or their biosimilars can lead to a variety of clinical effects including infusion reactions and local and systemic immune reactions. They are also associated with requirements for higher or more frequent drug doses, lower cost-effectiveness, reduced duration of response to treatment, and eventually drug failure. (See 'Clinical effects' above.)
•Impact of coadministration of TNF inhibitors with methotrexate – Coadministration of methotrexate (usually at least 10 mg weekly) and several other agents is associated with reduced circulating levels of ADA and increased drug levels in some infliximab- and adalimumab-treated patients. However, whether these changes are associated with improved clinical responsiveness may differ depending upon the underlying disease; this approach may be helpful in patients with rheumatoid arthritis (RA) but not for those with inflammatory bowel disease (IBD). (See 'Infliximab-induced human antichimeric antibodies' above and 'Adalimumab-induced human anti-human antibodies' above.)
●Therapeutic drug monitoring – Therapeutic drug monitoring (TDM) involves routinely assessing circulating drug and ADA levels for patients on prolonged therapy with certain TNF inhibitors. It can be proactive, where regular measurement of serum drug and ADA levels facilitates titration of therapy to a therapeutic range, or reactive, where serum drug and ADA levels are measured in the setting of a poor therapeutic response or decreasing clinical efficacy.
The clinical utility of TDM depends on the underlying condition, type of TNF inhibitor being used, phase of therapy (ie, induction versus maintenance), and TDM strategy (proactive versus reactive). As examples, increasing evidence supports proactive TDM for infliximab in maintenance therapy for IBD, with multiple improved clinical outcomes, and also for reactive TDM, with improvement in hospitalization rates and cost-effectiveness. (See 'Therapeutic drug monitoring' above and "Treatment of Crohn disease in adults: Dosing and monitoring of tumor necrosis factor-alpha inhibitors", section on 'Therapeutic drug monitoring'.)
●Autoimmunity
•Autoantibodies – The formation of autoantibodies such as antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA), and antiphospholipid antibodies has been reported in response to all biologic TNF inhibitors. (See 'Autoantibodies' above.)
•Autoimmune diseases – Cases of vasculitis, particularly cutaneous vasculitis, and lupus-like syndromes have been reported in association with biologic TNF inhibitor use. Most cases of vasculitis and systemic lupus erythematosus (SLE) reported in association with the use of a TNF inhibitor resolve following discontinuation of the TNF inhibitor. Other autoimmune conditions that may develop in association with the use of anti-TNF antibody constructs include psoriatic skin lesions, sarcoidosis, antiphospholipid syndrome, uveitis, interstitial lung disease (ILD), dermatomyositis (DM) and polymyositis (PM), demyelinating disease, peripheral neuropathies, and autoimmune hepatitis. (See 'Autoimmune diseases' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges John Stone, MD, and Klaus Bendtzen, MD, DMSc, who contributed to an earlier version of this topic review.
