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Research · Medication

TNF inhibitors

Cochrane and other meta-analyses found TNF inhibitors raised response rates against placebo or methotrexate alone in rheumatoid arthritis (about 1 more responder in 5 treated), ankylosing spondylitis, Crohn's disease and ulcerative colitis. Serious infections rose, and tuberculosis about doubled. Pooled trials disagree on cancer. Labels carry a boxed warning for serious infections and malignancy.

Add to Bio HackChecked 2026-11-14
Status
Prescription biologics in the US. Adalimumab, etanercept, certolizumab, golimumab and Zymfentra (infliximab) are injected under the skin, and Remicade and its biosimilars (infliximab) and Simponi Aria (golimumab) are given into a vein. FDA-approved uses vary by drug and include rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, plaque psoriasis, Crohn's disease, ulcerative colitis and juvenile idiopathic arthritis, with hidradenitis suppurativa and uveitis for adalimumab. Every label carries an FDA boxed warning for serious infections and malignancy.
Also called
adalimumab, Humira, adalimumab biosimilars, Amjevita, Cyltezo, Hadlima, Hyrimoz, Yusimry, Idacio, Yuflyma, Simlandi, etanercept, Enbrel, infliximab, Remicade, Inflectra, Renflexis, Avsola, Zymfentra, certolizumab pegol, Cimzia, golimumab, Simponi, Simponi Aria, anti-TNF, TNF blockers, TNF alpha inhibitors, biologics
Taken for
rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, back pain from spondylitis, psoriasis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, joint pain and swelling, autoimmune disease, hidradenitis suppurativa, uveitis

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help7

Reported risks12

What people take it for, and what was found

Shown to help7

StrongVery common

Rheumatoid arthritis

Shown to raise the share of people with a 50% improvement about 3-fold when added to methotrexate, about 1 more responder in every 5 treated.

Compared with methotrexate or another DMARD alone, or placebo [1][2][3]

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In a Cochrane network meta-analysis of 79 trials in people not helped enough by methotrexate, a TNF biologic plus methotrexate or another DMARD raised ACR50 response against the comparator (RR 3.23, 95% credible interval 2.75 to 3.79). For all biologics with methotrexate, 24% more patients responded (number needed to treat 5), 18% more reached remission (number needed to treat 6), and function improved 0.25 points more on a 0 to 3 scale [1]. Adalimumab 40 mg under the skin every other week with methotrexate raised ACR50 at 24 weeks (RR 4.63, 95% CI 3.04 to 7.05, number needed to treat 3) [2]. Etanercept under the skin plus a DMARD raised ACR50 against a DMARD alone in people with an inadequate response (RR 2.0, 95% CI 1.3 to 2.9, 38% absolute benefit) and slowed joint damage on x-rays [3].
Population
32,874 participants in 79 RCTs, mostly 6 to 12 months [1]; 2,381 patients in 6 trials [2]; 2,842 participants in 9 trials over 6 to 36 months [3].
Sources
[1], [2], [3]
Caveats
Evidence was moderate quality, downgraded for inconsistency [1]. Most trials were funded by the makers [3]. Infliximab is given into a vein and the others under the skin, and the pooled estimate covers all five drugs [1].
ModerateVery common

Psoriatic arthritis

Shown to raise joint and skin responses against placebo in psoriatic arthritis, with a 20% joint improvement in 58% against 14% in the main adalimumab trial.

Compared with placebo injections [4]; placebo or control treatment [5][6]

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
At week 12, ACR20 was reached by 58% on adalimumab 40 mg under the skin every other week and 14% on placebo. In people with psoriasis on at least 3% of the skin, 59% reached 75% skin clearing (PASI 75) at 24 weeks against 1%, and x-ray damage scores changed -0.2 against 1.0 [4]. A review of 9 RCTs found more people reached ACR20, ACR50, PsARC and PASI 75 on TNF inhibitors than on control for up to 24 weeks, with no difference between the TNF drugs [5]. In a network meta-analysis, infliximab, golimumab and etanercept were ahead of most other biologics on ACR response [6].
Population
313 adults with moderate to severe psoriatic arthritis and a poor response to NSAIDs, over 24 weeks [4]; 9 RCTs and 6 observational studies [5]; RCTs of biologics in people new to biologics [6].
Sources
[4], [5], [6]
Caveats
Graded Moderate, not Strong, because neither review's abstract gives a pooled effect size [5][6]. Etanercept and infliximab had more injection or infusion site reactions [5].
ModerateVery common

Ankylosing spondylitis

Shown to make a 40% improvement in spine symptoms 3 to 4 times as likely as placebo by 6 months, with 3 to 5 people treated for one extra response.

Compared with placebo [7]

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
By 6 months, ASAS40 response was more likely than on placebo with adalimumab (RR 3.53, 95% credible interval 2.49 to 4.91), etanercept (RR 3.31), golimumab (RR 2.90) and infliximab (RR 4.07), a 25% to 40% absolute difference and a number needed to treat of 3 to 5. Physical function improved 1.1 to 2.1 points more on a 0 to 10 scale. Partial remission was more likely, with a number needed to treat of 3 to 11 [7].
Population
3,308 participants in 21 RCTs of 24 weeks or less [7].
Sources
[7]
Caveats
Trials were short and most were funded by drug makers. One trial measuring x-ray progression found no difference with etanercept [7].
Moderate

Plaque psoriasis

Shown to raise the share reaching 90% skin clearing against placebo in moderate to severe psoriasis, though IL-17 and IL-23 drugs mostly reached it more often.

Compared with placebo, and other systemic and biologic drugs in a network analysis [8]

The numbers and sources
Effect
Across 179 RCTs, every class, anti-TNF included, reached PASI 90 more often than placebo. Infliximab, given into a vein, ranked highest against placebo (RR 49.16, 95% CI 20.49 to 117.95, high certainty). Infliximab, IL-17 drugs and most IL-23 drugs were more likely to reach PASI 90 than ustekinumab and three other anti-TNF drugs. Adalimumab was ahead of etanercept, and ustekinumab ahead of certolizumab. Serious adverse events did not differ from placebo for any drug [8].
Population
62,339 adults with moderate to severe plaque psoriasis in 179 RCTs, mostly 8 to 24 weeks [8].
Sources
[8]
Caveats
Most trials were short and 138 of 179 declared drug company funding [8].
Strong

Crohn's disease

Shown to raise remission against placebo in moderate to severe Crohn's disease, about 1.7 to 1.9 times as often for induction and maintenance.

Compared with placebo [9][10]

The numbers and sources
Effect
Against placebo, anti-TNF drugs raised induction of remission (RR 1.66, 95% CI 1.17 to 2.36) and maintenance of remission (RR 1.78, 95% CI 1.51 to 2.09) [9]. A second meta-analysis found more remission at week 4 (RB 1.90, 95% CI 1.55 to 2.33), at weeks 20 to 30 (RB 1.86) and at weeks 48 to 56 (RB 2.75, 95% CI 2.13 to 3.54), and more fistula healing [10].
Population
10 trials of infliximab (into a vein), adalimumab and certolizumab (under the skin) [9]; 19 trials [10].
Sources
[9], [10]
Caveats
Neither review compared these drugs with newer non-TNF biologics.
Strong

Ulcerative colitis

Shown to raise remission against placebo in moderate to severe ulcerative colitis, with infliximab about 3 times as likely to bring remission at 8 weeks.

Compared with placebo [11][12]; placebo and other biologics and small molecules in network analyses [12][13]

The numbers and sources
Effect
In people not helped by steroids or immunosuppressants, three infliximab infusions into a vein raised clinical remission at 8 weeks (RR 3.22, 95% CI 2.18 to 4.76) and endoscopic remission (RR 1.88), and one infusion lowered colectomy within 90 days (RR 0.44, 95% CI 0.22 to 0.87) [11]. In a network meta-analysis, adalimumab, golimumab, infliximab and vedolizumab all led to more response, remission and mucosal healing than placebo, and infliximab gave more response than adalimumab (OR 2.36) [12]. In a network meta-analysis of 28 trials, infliximab 5 and 10 mg/kg ranked second and third for clinical remission behind upadacitinib, and infliximab 10 mg/kg ranked first for endoscopic improvement (RR of failure 0.61, 95% CI 0.51 to 0.72) [13].
Population
7 RCTs in moderate to severe disease [11]; 7 placebo-controlled induction trials [12]; 12,504 patients in 28 trials [13].
Sources
[11], [12], [13]
Caveats
The largest effects are for infliximab, and the Cochrane review is from 2006 [11]. Maintenance trials were judged at high risk of bias [12].
Limited

Switching to a biosimilar

One trial found switching from originator infliximab to the biosimilar CT-P13 was not worse than staying on the originator, with disease worsening in 30% against 26%.

Compared with continued originator infliximab [16]

The numbers and sources
Effect
Over 52 weeks, disease worsened in 26% who stayed on originator infliximab and 30% who switched (adjusted difference -4.4%, 95% CI -12.7 to 3.9), within the 15% non-inferiority margin. Serious adverse events (10% against 9%) and stopping for adverse events (4% against 3%) were similar [16].
Population
482 adults on stable infliximab infusions for Crohn's disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis or psoriasis in Norway [16].
Sources
[16]
Caveats
The trial was not powered to show non-inferiority within each disease [16]. It tested one infliximab biosimilar, not the adalimumab or etanercept biosimilars. It was funded by the Norwegian Ministry of Health [16].

Mixed results1

Moderate

Differences between TNF inhibitors

Mixed results: indirect comparisons mostly found similar effects, but infliximab ranked higher in psoriasis and ulcerative colitis, and etanercept led to fewer withdrawals for side effects.

Compared with other TNF inhibitors, indirectly in network analyses [14][7][8][9][12] and directly in one trial [15]

The numbers and sources
Effect
In rheumatoid arthritis, indirect comparisons found similar ACR50 response across TNF drugs, while adalimumab (ratio of ORs 1.89) and infliximab led to more withdrawals for side effects than etanercept [14]. In a 125-person head-to-head trial, 65% stayed on adalimumab and 56.7% on etanercept at 52 weeks, and adalimumab was judged not inferior [15]. In psoriasis, adalimumab reached PASI 90 more often than etanercept, and infliximab more often than three other anti-TNF drugs [8]. In Crohn's disease, adalimumab was ahead of certolizumab for induction of remission (RR 2.93, 95% credible interval 1.21 to 7.75) [9]. In ulcerative colitis, infliximab gave more response than adalimumab (OR 2.36) [12]. In ankylosing spondylitis, differences between drugs were inconclusive [7].
Population
Cochrane reviews of RA trials [14]; 125 adults with active RA [15]; network analyses in psoriasis [8], Crohn's disease [9], ulcerative colitis [12] and ankylosing spondylitis [7].
Sources
[14], [15], [8], [9], [12], [7]
Caveats
Almost all comparisons are indirect. The only head-to-head trial was unblinded and small [15]. Infliximab is given into a vein at weight-based doses, so it is not compared at like-for-like routes.

Doses studied

The rheumatoid arthritis trials used adalimumab 40 mg under the skin every other week [2] and etanercept 10 or 25 mg under the skin twice weekly [3]. The head-to-head trial used adalimumab 40 mg every other week and etanercept 50 mg weekly [15], and the psoriatic arthritis trial used adalimumab 40 mg every other week [4]. The adalimumab label gives 40 mg every other week for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, and 160 mg, then 80 mg, then 40 mg every other week for adult Crohn's disease [17]. The etanercept label gives 50 mg weekly, with 50 mg twice weekly for the first 3 months in adult psoriasis [18]. The infliximab label gives infusions into a vein of 5 mg/kg at weeks 0, 2 and 6 and then every 8 weeks for Crohn's disease and ulcerative colitis, and 3 mg/kg with methotrexate for rheumatoid arthritis [19]. The certolizumab label gives 400 mg at weeks 0, 2 and 4, then 200 mg every other week for rheumatoid arthritis [20], and the golimumab label gives 50 mg under the skin once a month for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis [21].

Risks

Reported risks11

ModerateVery common

Injection site and infusion reactions

Shown to raise injection site reactions, 37% on etanercept against 11% on placebo, and infusion reactions, about 20% on infliximab against 10%.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In placebo-controlled trials, 20% on adalimumab had injection site reactions (redness, itching, bleeding, pain or swelling) against 14% on placebo, mostly mild [17]. In rheumatoid arthritis trials, injection site reactions occurred in 37% on etanercept and 11% on placebo, mostly in the first month and lasting 3 to 5 days [18]. About 20% given infliximab into a vein had an infusion reaction against 10% on placebo, serious infusion reactions including anaphylaxis occurred in under 1%, and about 3% stopped because of them [19].
Population
Placebo-controlled trial pools on each label: 349 on etanercept and 152 on placebo in RA [18]; adalimumab [17] and infliximab [19] trial pools.
Sources
[17], [18], [19]
Caveats
Label trial pools, not an independent meta-analysis.
ModerateCommon

Stopping for side effects and serious adverse events

Shown to raise stopping for side effects in ankylosing spondylitis trials, 2.3% against 0.7%, and serious adverse events slightly with TNF drugs plus methotrexate in rheumatoid arthritis.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In ankylosing spondylitis, 38 of 1,637 people on an anti-TNF drug and 7 of 986 on placebo withdrew for adverse events (Peto OR 2.44, 95% CI 1.26 to 4.72), and serious adverse events did not differ significantly (Peto OR 1.45, 95% CI 0.85 to 2.48) [7]. In RA, a TNF biologic plus methotrexate raised serious adverse events against the comparator (Peto OR 1.20, 95% credible interval 1.01 to 1.43, moderate quality), while withdrawals for adverse events were inconclusive (RR 1.24) [1].
Population
16 RCTs in ankylosing spondylitis [7]; 79 RCTs in RA [1].
Sources
[7], [1]
Caveats
Low event rates and short trials [7].
ModerateCommon

Raised liver enzymes and liver injury

Shown to raise ALT to 3 times normal or more in 3.5% on adalimumab against 1.5% on control. The infliximab label warns of severe liver reactions, some fatal.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In controlled trials in RA, psoriatic arthritis and ankylosing spondylitis, ALT rose to 3 times the upper limit of normal or more in 3.5% on adalimumab 40 mg every other week and 1.5% on control [17]. In children with Crohn's disease on infliximab, ALT rose up to 3 times normal in 18% and to 3 times or more in 4%. The infliximab label warns of severe liver reactions, some fatal or needing a transplant [19]. Both labels warn of hepatitis B reactivation in chronic carriers, in some cases fatal, mostly in people also on other immunosuppressants [17][19].
Population
Controlled trials of 4 to 104 weeks [17]; children in Crohn's trials followed a median 53 weeks [19].
Sources
[17], [19]
Caveats
Many trial subjects also took drugs that raise liver enzymes, such as NSAIDs and methotrexate, so the label says the link to adalimumab is not clear [17].
StrongUncommon

Tuberculosis

Shown to raise tuberculosis about 2-fold in pooled trials, 0.57% on TNF inhibitors against 0.08% on control. The labels require testing for latent TB first.

The numbers and sources
How common
Uncommon: between 1 in 1,000 and 1 in 100 people.
Effect
Across 29 RCTs, 45 of 7,912 people on TNF inhibitors (0.57%) and 3 of 3,967 on control developed TB (OR 1.94, 95% CI 1.10 to 3.44), with a higher risk in RA (OR 2.29) [25]. Across 71 RCTs, TB rose 250% [23]. In adalimumab's global trials the rate of active TB was 0.20 per 100 patient-years, and most cases began within 8 months of starting, consistent with reactivated latent infection [17].
Population
11,879 patients in 29 RCTs of infliximab, adalimumab, golimumab, etanercept and certolizumab [25]; 22,760 participants in 71 RCTs [23]; 24,605 adalimumab-treated subjects [17].
Sources
[25], [23], [17]
Caveats
GRADE rated the evidence low [25]. Rates were lower in the US and Canada than worldwide [17].
StrongHow often is not known

FDA boxed warning: serious infections

FDA states users face increased risk of serious infections that may lead to hospitalization or death. Pooled trials found serious infections about 1.3 to 2 times as often.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The boxed warning lists active tuberculosis including reactivation of latent TB, invasive fungal infections such as histoplasmosis, and bacterial, viral and opportunistic infections including Legionella and Listeria. It says most people who developed these infections were also taking immunosuppressants such as methotrexate or corticosteroids. In adalimumab's controlled trials, serious infections occurred at 4.3 per 100 patient-years against 2.9 on control [17]. Pooling 9 RCTs of infliximab and adalimumab in RA, the odds of serious infection were 2.0 (95% CI 1.3 to 3.1), with one extra serious infection for every 59 people treated over 3 to 12 months [22]. Across 71 RCTs in RA, psoriatic arthritis and ankylosing spondylitis, serious infections rose 40% and any infection 20% [23]. In a network meta-analysis of 106 RA trials, standard-dose biologics raised serious infections against traditional DMARDs (OR 1.31, 95% credible interval 1.09 to 1.58), and high doses more (OR 1.90), about 6 more serious infections per 1,000 patients a year at standard dose [24].
Population
7,973 adalimumab-treated and 4,848 control subjects in controlled trials [17]; 3,493 on anti-TNF antibodies and 1,512 on placebo [22]; 22,760 participants in 71 RCTs [23]; 106 RCTs of biologics in RA [24].
Sources
[17], [22], [23], [24]
Caveats
[24] covers all biologics in RA, not TNF inhibitors alone. Trial follow-up was mostly 1 year or less [22][23].
LimitedHow often is not known

Lymphoma in inflammatory bowel disease

Linked to about 2.4 times the lymphoma risk with anti-TNF drugs alone and 6.1 times combined with thiopurines, in a national cohort of adults with bowel disease.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Lymphoma occurred at 0.26 per 1,000 person-years in unexposed patients, 0.41 on anti-TNF monotherapy and 0.95 on anti-TNF plus a thiopurine (azathioprine or mercaptopurine). Against unexposed patients, adjusted hazard ratios were 2.41 (95% CI 1.60 to 3.64) for anti-TNF alone, 2.60 for thiopurines alone and 6.11 (95% CI 3.46 to 10.8) for the combination [27].
Population
189,289 adults with inflammatory bowel disease in French national insurance data, followed a median 6.7 years [27].
Sources
[27]
Caveats
Observational. The absolute rates were low [27].
ModerateHow often is not known

Skin cancer

Linked to about 28% more non-melanoma skin cancer in people with rheumatoid arthritis, mainly squamous cell. A rise in melanoma was not statistically significant.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Against people with RA not on anti-TNF drugs, users had more non-melanoma skin cancer (RR 1.28, 95% CI 1.19 to 1.38) and squamous cell cancer (RR 1.30), but not basal cell cancer (RR 1.13, 95% CI 0.97 to 1.31) [28]. Against conventional systemic drugs, biologic treatment gave nonsignificant pooled relative risks of melanoma of 1.20 in IBD, 1.20 in RA (95% CI 0.83 to 1.74) and a hazard ratio of 1.57 in psoriasis [29].
Population
123,031 patients with RA in 6 prospective observational studies [28]; 34,029 biologic-treated and 135,370 biologic-naive patients in 7 cohort studies [29].
Sources
[28], [29]
Caveats
Observational studies. Most melanoma studies did not adjust for other risk factors, and the authors say a clinically important rise cannot be ruled out [29]. [29] covers all biologics.
LimitedHow often is not known

Heart failure

One trial found infliximab 10 mg/kg into a vein raised death or heart failure hospitalization 2.8-fold in moderate to severe heart failure. Labels warn of worsening heart failure.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Over 28 weeks, the combined risk of death or hospitalization for heart failure rose with infliximab 10 mg/kg (HR 2.84, 95% CI 1.01 to 7.97), and 20 people on 10 mg/kg, 10 on 5 mg/kg and 13 on placebo were hospitalized for any reason [30]. Infliximab above 5 mg/kg is contraindicated in moderate or severe heart failure [19]. The adalimumab label reports cases of new and worsening congestive heart failure with TNF blockers [17].
Population
150 adults with class III or IV heart failure and ejection fraction of 35% or less [30]; label reports [17][19].
Sources
[30], [19], [17]
Caveats
One small pilot trial in people with heart failure, not in people with arthritis or bowel disease [30].
LimitedHow often is not known

Nerve, blood and autoimmune reactions

The labels warn of rare demyelinating disease, including multiple sclerosis, optic neuritis and Guillain-Barré syndrome, low blood counts and a lupus-like syndrome.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
TNF blockers have been linked to new or worse central demyelinating disease, including multiple sclerosis and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. The labels describe a lupus-like syndrome and autoimmune hepatitis, which are reasons to stop [17]. Leukopenia, neutropenia, thrombocytopenia and pancytopenia, some fatal, have been reported with infliximab, with an unclear causal link [19]. Positive antinuclear antibodies were more common on adalimumab than placebo [2].
Population
Postmarketing and trial reports [17][19]; 2,381 patients in adalimumab RA trials [2].
Sources
[17], [19], [2]
Caveats
Case reports give no rate [17][19].
LimitedHow often is not known

With other biologics and immune-suppressing drugs

The labels advise against combining TNF inhibitors with anakinra, abatacept or another TNF blocker because of possible added infection risk.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The adalimumab label advises against combining it with other biologic DMARDs such as anakinra and abatacept, or with other TNF blockers, because of a possible increased risk of infections. It notes a higher rate of serious infections in RA patients given a TNF blocker after rituximab [17]. Almost all cases of hepatosplenic T-cell lymphoma occurred with azathioprine or 6-mercaptopurine as well [17]. In network meta-analysis, combination biologic therapy added about 55 serious infections per 1,000 patients a year against traditional DMARDs [24].
Population
Label reports [17]; 106 RCTs in RA [24].
Sources
[17], [24]
Caveats
Little trial data on combinations [17].
ModerateStudied in pregnancyHow often is not known

Use in pregnancy and live vaccines in infants

Linked to more preterm births, odds 1.45, and slightly more newborn infections after exposure in pregnancy, against mothers with the same diseases. Certolizumab showed almost no placental transfer.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
Against mothers with the same diseases not exposed, exposure in pregnancy was linked to preterm birth (OR 1.45, 95% CI 1.16 to 1.82) and newborn infections (OR 1.12, 95% CI 1.00 to 1.27). In inflammatory bowel disease, preterm birth (OR 1.66) and low birth weight (OR 1.49) rose, while pooled RA and psoriasis data showed no rise in adverse outcomes [31]. In 14 infants of mothers on certolizumab, 13 had no measurable drug at birth and 1 a minimal level [32]. Infliximab crosses the placenta and was detected in infants up to 6 months after birth, and the label advises waiting at least 6 months before live vaccines in exposed infants [19].
Population
39 studies of women with immune-mediated diseases [31]; 16 women at 30 weeks or more of pregnancy on certolizumab and their infants [32]; label [19].
Sources
[31], [32], [19]
Caveats
Observational. Disease activity itself raises some of these risks, and controls were women with the same diseases [31].

Mixed results1

ModerateHow often is not known

FDA boxed warning: malignancy

FDA states lymphoma and other cancers, some fatal, have been reported in children and teens on TNF blockers. Pooled adult trials disagree on whether overall cancer rises.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The boxed warning describes lymphoma and other malignancies in children and adolescents and postmarketing cases of hepatosplenic T-cell lymphoma, aggressive and fatal, mostly in adolescent and young adult males with Crohn's disease or ulcerative colitis, almost all also on azathioprine or 6-mercaptopurine. In adalimumab's controlled trials, cancers other than non-melanoma skin cancer occurred at 0.7 per 100 patient-years on both adalimumab and control, and lymphoma at about 0.11 per 100 patient-years, about 3 times the expected US rate [17]. Pooling 9 RCTs of infliximab and adalimumab in RA, malignancy odds were 3.3 (95% CI 1.2 to 9.1), higher at higher doses, with one extra cancer per 154 treated over 6 to 12 months [22]. Pooling 55 RCTs in RA, psoriatic arthritis and ankylosing spondylitis found no association with cancer (random-effects OR 1.16, 95% CI 0.75 to 1.81) [26]. The Cochrane network meta-analysis found results inconclusive for cancer with TNF biologics plus methotrexate (Peto OR 1.21, 95% credible interval 0.63 to 2.38) [1].
Population
Postmarketing reports and adalimumab trial pools [17]; 5,005 patients in 9 RCTs [22]; 20,631 patients in 55 RCTs [26]; 79 RCTs [1].
Sources
[17], [22], [26], [1]
Caveats
Trials were short for a cancer outcome. [26] found signs of reporting or publication bias and judged its evidence imprecise. People with rheumatoid arthritis have a higher background lymphoma rate [17].

Claims tested and not found

  1. That blocking TNF helps heart failure. In a randomized trial, neither infliximab dose improved clinical status at 14 weeks, despite lower inflammatory markers, and 10 mg/kg raised death or heart failure hospitalization [30].
  2. That switching from originator infliximab to a biosimilar worsens disease control. Disease worsening was 26% on the originator and 30% after switching, within the trial's non-inferiority margin [16].
  3. That TNF inhibitors raise overall cancer in short trials in arthritis and spondylitis. Pooling 55 RCTs found no association (OR 1.16, 95% CI 0.75 to 1.81) [26], although an earlier pooling of infliximab and adalimumab trials did find one [22].

Sources

  1. Singh JA, Hossain A, Tanjong Ghogomu E, et al. Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis. Cochrane Database of Systematic Reviews. 2016. https://doi.org/10.1002/14651858.cd012183
  2. Navarro-Sarabia F, Ariza-Ariza R, Hernandez-Cruz B, Villanueva I. Adalimumab for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2005. https://doi.org/10.1002/14651858.cd005113.pub2
  3. Lethaby A, Lopez-Olivo MA, Maxwell L, et al. Etanercept for the treatment of rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2013. https://doi.org/10.1002/14651858.cd004525.pub2
  4. Mease PJ, Gladman DD, Ritchlin CT, et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis & Rheumatism. 2005. https://doi.org/10.1002/art.21306
  5. Lemos LL, de Oliveira Costa J, Almeida AM, et al. Treatment of psoriatic arthritis with anti-TNF agents: a systematic review and meta-analysis of efficacy, effectiveness and safety. Rheumatology International. 2014. https://doi.org/10.1007/s00296-014-3006-2
  6. Ruyssen-Witrand A, Perry R, Watkins C, et al. Efficacy and safety of biologics in psoriatic arthritis: a systematic literature review and network meta-analysis. RMD Open. 2020. https://doi.org/10.1136/rmdopen-2019-001117
  7. Maxwell LJ, Zochling J, Boonen A, et al. TNF-alpha inhibitors for ankylosing spondylitis. Cochrane Database of Systematic Reviews. 2015. https://doi.org/10.1002/14651858.cd005468.pub2
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