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Abstract

Background:

Tumor necrosis factor-alpha (TNF-α) is implicated in the pathogenesis of autoimmune conditions and sepsis. Although anti-TNF-α therapies have demonstrated clinical efficacy in rheumatoid arthritis (RA), there is no established evidence for benefit in patients with sepsis.

Objectives:

We sought to quantify circulating TNF-α in patients with RA and compare results to TNF-α levels in sepsis.

Design:

We performed a systematic review and meta-analysis of circulating TNF-α in patients with RA. We searched Cochrane Library, Google Scholar, Ovid Embase, Ovid MEDLINE, Scopus, and Web of Science Core Collection databases from inception until May 30, 2023. We included randomized controlled studies and observational reports containing more than ten subjects that reported mean serum or plasma TNF-α levels. We used the Newcastle-Ottawa Scale to assess methodological quality of studies.

Data sources and methods:

Summary data were extracted and analyzed using a random-effects model to estimate the pooled mean circulating TNF-α. Circulating TNF-α in RA was compared to TNF-α levels reported in our systematic review and meta-analysis characterizing cytokine levels in sepsis.

Results:

We identified and screened 8764 studies, and 104 studies satisfied the inclusion criteria (5399 total participants, including 4419 females). Pooled estimated mean RA TNF-α was 23.1 pg/mL (95% CI 17.8–30.1) in the random-effects model. There was significantly lower TNF-α in RA patients using disease-modifying antirheumatic drugs (DMARDs, p = 0.04) and patients using corticosteroids (p = 0.01). After adjustment for age and sex, there was no significant difference between TNF-α in RA compared to sepsis.

Conclusion:

No significant difference between adjusted TNF-α levels in patients with RA versus sepsis was determined. Since TNF-α antagonists show benefit in RA but not sepsis despite comparable circulating concentrations, we conclude TNF-α does not contribute to sepsis pathogenesis. TNF-α concentration may be slightly higher due to study heterogeneity.

Trial registration:

This investigation was registered in PROSPERO (CRD42023425361).

Plain language summary

A comparison of tumor necrosis factor alpha levels in rheumatoid arthritis and sepsis

This study looked at the levels of a cytokine called tumor necrosis factor alpha (TNF-α) in the blood of patients with rheumatoid arthritis (RA) and compared them to levels found in patients with sepsis, a life-threatening infection. TNF-α is known to play a causative role in autoimmune diseases and is thought to play a role in causing sepsis. We identified 104 studies with 5,399 participants to measure TNF-α in RA patients. We found that the average TNF-α level in RA patients was 23.1 pg/mL. Patients who were using certain RA treatments like disease-modifying drugs or steroids had lower TNF-α levels. When comparing TNF-α levels in RA and sepsis, we found no major differences after considering age and sex. This suggests that even though TNF-α is increased in both RA and sepsis patients, it may not be as important in causing sepsis. TNF-α levels could vary slightly because of differences between the studies. In conclusion, while TNF-α plays a role in RA, it likely doesn't contribute to the development of sepsis despite similar TNF-α levels in both conditions.

Keywords

cytokines endotoxin infection rheumatoid arthritis sepsis tumor necrosis factor alpha tumor necrosis factor inhibitor

Introduction

Nineteenth-century physicians noted necrosis and regression of malignant tumors in patients with concurrent bacterial infections.¹ Subsequent work showed microbial products such as endotoxin (lipopolysaccharide, LPS), a component of gram-negative cell walls, augmented host response to tumor cells. Host anti-neoplastic activity was found to be mediated by an endogenous glycoprotein, subsequently named “tumor necrosis factor-alpha” (TNF-α).² Additional studies revealed striking sequence homology between TNF-α and cachectin, a factor involved in chronic wasting in patients with infections.³

Separately, endotoxin had long been implicated as a cause of systemic inflammation characterized by fever, hypotension, and multiorgan failure that resembled clinical sepsis.^4,5 These effects were associated with macrophage activation and secretion of TNF-α, implying a causative role for the host response in sepsis pathogenesis.⁶ This was supported when passive immunization of mice with antiserum or purified immune globulin directed against TNF-α prior to intraperitoneal injection of 400 µg of LPS provided significant mortality protection.⁷ Further study in animal models confirmed that the lethal effects of endotoxin were mediated by TNF-α.⁸ In a landmark study, Tracey et al injected cachectin doses up to 3.6 mg/kg body weight into rat tail veins with resultant hypotension, metabolic acidosis, respiratory failure, and death.⁹ Rats given 4 mg of TNF-α-neutralizing monoclonal antibody intravenously 1 h prior to cachectin infusion were protected. Collectively, these reports suggested TNF-α, synthesized in response to endotoxin, caused systemic inflammation and mediated sepsis pathogenesis, and it appeared TNF-α blockade would be a breakthrough in sepsis treatment.

Numerous anti-endotoxin^10,11 and anti-TNF-α therapies^12,13 were employed in animal models and human trials of sepsis. Despite early promise in animal studies, repeated human clinical trials failed to show convincing benefit, and one study showed increased mortality when using a TNF-α-neutralizing drug as sepsis treatment.¹⁴ Decades of failure of anti-TNF-α and other anti-inflammatory therapies for sepsis treatment have not diminished interest in their use. We have discussed the unexplained persistence of this concept in separate publications.^15,16

Rationale for using anti-cytokine therapies to treat sepsis relies on the concept that the host systemic inflammatory response to infection causes organ malfunction and death. Since cytokines TNF-α and IL-1 promote inflammation, they are invoked as causes of sepsis despite limited evidence that levels are sufficiently elevated to cause organ malfunction or death. In our attempt to understand the relationship between TNF-α and sepsis, we previously published a systematic review and meta-analysis characterizing levels of proinflammatory cytokines in sepsis and healthy volunteers.¹⁷ We calculated the pooled mean estimated TNF-α concentrations of 58.4 pg/mL in patients with sepsis and 5.5 pg/mL in healthy volunteers.

Comparing TNF-α levels in sepsis to levels in non-sepsis conditions is necessary to understand the role (if any) of TNF-α in sepsis pathogenesis and answer the question, “Is that a lot?” Rheumatoid arthritis (RA) is a prototypical inflammatory/autoimmune disease for which anti-TNF-α therapies have shown unequivocal benefit.^18,19 Despite the clinical importance of TNF-α in RA, no meta-analysis of TNF-α levels has previously been conducted. Therefore, we sought to evaluate circulating levels of TNF-α in patients with RA and compare them to circulating levels of TNF-α in patients with sepsis.

Methods

Study design and inclusion criteria

We performed a systematic review and meta-analysis of studies reporting serum or plasma (circulating) TNF-α levels in patients with RA. This review and meta-analysis considered longitudinal studies, prospective cohort studies, randomized and nonrandomized clinical trials, case-control studies, time-series studies, case series, and descriptive cross-sectional studies. We excluded case reports to minimize publication bias. The studies must have included TNF-α concentrations in serum or plasma and expressed in mass units per volume. Tumor necrosis factor-alpha concentrations measured using enzyme-linked immunosorbent assay (ELISA) or immunologic/magnetic bead technology were included. Quantified data depicted only in graphical form were excluded. Participant study subjects of any age, ethnicity, or sex were included.

This investigation was reported in alignment with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline (Supplemental Table 1).²⁰

Information sources

A systematic search of the literature was conducted by a medical librarian (AAG). The following electronic databases were searched: Cochrane Library, Google Scholar, Ovid Embase, Ovid MEDLINE, Scopus, and Web of Science Core Collection databases to find relevant articles published from the inception of each database until May 30, 2023. The search was peer-reviewed by a second medical librarian (T.M.) using the Peer Review of Electronic Search Strategies (PRESS) guideline.²¹ Databases were searched using a combination of controlled vocabulary and free text terms for RA and tumor necrosis factor testing. The search was not limited by language, publication type, or year (Supplemental Table 2).

Data selection, collection, and management

All identified studies were uploaded into EndNote X9 (Clarivate Analytics, Philadelphia, PA, USA) and Covidence. Duplicate studies were removed. Two reviewers independently screened titles and abstracts of studies for eligibility and data extraction. Next, two reviewers independently evaluated the full-text articles for inclusion/exclusion criteria. Discrepancies were resolved by a third reviewer if a consensus was not reached. Through Covidence, we generated a PRISMA document containing the initial number of reports, the number excluded during title/abstract screening, and the number excluded during full-text assessments, along with reasons for exclusion (Supplemental Table 3). Following the selection protocol, the collected reports were included in the final report.

Data were accrued using a standardized extraction form. Extracted data consisted of type of study, TNF-α measurement methodology, number of participants, RA duration in years, presence or absence of RA treatment, type of RA treatment (nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), corticosteroids, or TNF-α inhibitors), markers of inflammation or RA severity (mean C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), or Disease Activity Score-28 with ESR (DAS28-ESR) values), additional comorbidities (e.g., diabetes mellitus, cardiovascular disease, hepatic or renal failure, and malignancy), presence of other autoimmune or inflammatory diseases, and circulating TNF-α levels. Study data were collected and managed using Research Electronic Data Capture tools (REDCap). Two independent people were involved with data extraction. Disagreements were resolved by the assessment of a third reviewer. All extraction forms, tools, and meta-analyses were pilot-tested in two studies and subsequently modified to ensure the extraction of relevant data and confirm the feasibility of our research question. If any data were missing in the study or if uncertainties arose, we attempted to contact the study authors for clarification. All reports except four reported TNF-α concentrations as picograms per milliliter (pg/mL). In these studies, TNF-α was expressed as nanograms per milliliter (ng/mL). We assumed these concentrations were in fact pg/mL for two reasons. First, this type of reporting error is not uncommon (personal experience of authors). Second, ng/mL values differ from those of all other reports by three orders of magnitude, which is unlikely.

Risk of bias across studies

Two reviewers independently evaluated the included studies for risk of bias, and a third reviewer resolved disagreements. The same two reviewers independently assessed methodological quality of included studies according to the Newcastle-Ottawa Scale (NOS) tool. The NOS tool judges each study on eight items, separated into three categories: selection of study groups, comparability of study groups, and ascertainment of either exposure or outcome of interest for case-control or cohort studies. Stars awarded for each quality item serve as a quick visual assessment; the highest quality studies are awarded up to nine stars.

Statistical analysis

We extracted mean and standard deviation for TNF-α concentration in individual studies, calculated the standard error of the mean, and then log-transformed the mean values. Tumor necrosis factor-alpha concentrations were expressed in picograms per milliliter (pg/mL). We entered each study’s log-transformed mean and standard error into a random-effects analysis that combined mean log values and determined the pooled effect size. Results were back-transformed for interpretation. Between-study heterogeneity was estimated using the I² statistic, where a larger I² indicates increased study heterogeneity. Subgroup and metaregression analyses examined factors associated with cytokine levels and factors contributing to study heterogeneity. When high heterogeneity was obtained (I² ⩾ 60%), we performed a subgroup analysis or removed selected studies to determine the source of high heterogeneity. Linearity between TNF-α levels and continuous outcome variables was evaluated using a scatter plot. We conducted a sensitivity analysis to investigate the effect of individual studies on pooled outcomes. Pooled effect was recalculated after excluding one study from the analysis and repeating this single-study exclusion for each included study. We compared TNF-α levels in RA studies with those in sepsis determined in our previous systematic review and meta-analysis.¹⁷ We also compared levels in these two diseases after adjusting TNF-α levels for age and sex using metaregression to more accurately compare TNF-α in RA and sepsis. This adjustment is especially important since RA is a disease with significant female predominance.²² Global estimates show female predominance in sepsis of approximately 1.1 to one,²³ compared to approximately 2.45 to one female predominance in RA.²⁴ Contour-enhanced funnel plots were constructed to assess publication bias, and the Egger test evaluate for a small-study effect. Statistical analyses were performed using Stata software, version 16.0 (StataCorp, College Station, TX, USA).

There was no funding source for this study.

Results

Literature search for RA studies

Database searches yielded 8764 citations. After removing duplicates, 5209 citations underwent title/abstract screening. Of these, 683 reports met criteria for full-text review. One paper could not be retrieved, and 578 papers were eliminated (Figure 1). A total of 104 studies met the inclusion criteria and comprised 51 (49.0%) cross-sectional studies, 18 (17.3%) randomized controlled trials (RCTs), 17 (16.3%) case-control reports, 13 (12.5%) case series, and 5 (4.8%) cohort studies.^25–128 Included studies contained a total of 5399 participants. Mean number of participants in each study was 51.9, with a minimum of 10 and a maximum of 261. Mean age of participants was 50.2 years, with a minimum of 30 years and a maximum of 70 years. Our analysis included 4419 (81.8%) female subjects (Supplemental Table 4).

Figure 1.

PRISMA flowchart.

TNF-α levels in RA and subgroup analysis (random-effects model)

In the random-effects model analysis, the overall mean TNF-α concentration was 23.1 pg/mL, with mean TNF-α levels ranging from 1.2 to 823.2 pg/mL (Figure 2). Mean TNF-α concentration by study type was: 26.8 pg/mL in cross-sectional studies, 14.7 pg/mL in RCTs, 29.0 pg/mL in case-control reports, 17.7 pg/mL in case series, and 24.5 pg/mL in cohort studies. There was no significant difference in TNF-α level by study type (p = 0.31). The TNF-α concentration was 22.8 pg/mL in studies using ELISA to measure TNF-α (99 studies or 95.2%) and 30.7 pg/mL in studies using immunologic bead assays to measure TNF-α (five reports or 4.8%; p = 0.68). Mean TNF-α was 17.9 pg/mL in studies using venous blood sampling (37 studies or 35.6%) compared to 26.6 pg/mL in studies with unspecified blood sampling (67 studies or 64.4%; p = 0.14). In Asian studies (seven reports or 6.7%), the TNF-α concentration was 18.4 pg/mL compared to 23.5 pg/mL in non-Asian studies (97 reports or 93.3%; p = 0.631). These results are summarized in Table 1. Included studies by country of origin are displayed in Supplemental Figure 1.

Figure 2.

Forest plot of TNF-α levels in RA grouped by study type and quality assessment score.

Table 1.

Subgroup analysis for TNF-α levels in rheumatoid arthritis studies.

Group	Studies (N)	TNF (pg/mL) (95% CI)	p-Value
Technique			0.675
ELISA	99	22.8 (17.4 to 29.9)
Immunologic	5	30.7 (7.8 to 121.1)
Type of sample			0.141
Venous	37	17.9 (11.9 to 26.8)
Nonspecified	67	26.6 (18.9 to 37.5)
Study location			0.631
Non-Asian study	97	23.5 (17.9 to 31.0)
Asian study	7	18.4 (7.0 to 48.4)
Any additional comorbidity			0.076
Yes	8	40 (25.6 to 62.5)
No	87	21.8 (16.2 to 29.2)
Unknown	9	33.9 (9.7 to 118.4)
Presence of AI condition			0.273
No	100	22.7 (17.3 to 29.9)
Yes	4	35.5 (16.8 to 74.8)
RA therapy			0.183
Yes	67	18.7 (13.7 to 25.5)
No	31	32.5 (19.6 to 54.1)
Unknown	6	25.1 (6.9 to 91.0)
DMARDs			0.038
No	41	33.0 (20.7 to 52.6)
Yes	63	18.3 (13.5 to 24.8)
NSAIDs			0.611
No	87	24.0 (18.2 to 31.6)
Yes	17	19.3 (8.7 to 42.6)
Corticosteroids			0.009
No	81	27.4 (20.3 to 36.9)
Yes	23	12.7 (7.7 to 20.8)
TNFi			0.553
No	98	23.6 (18.0 to 31.0)
Yes	6	16.4 (5.1 to 52.7)

AI, auto-inflammatory or autoimmune condition; CI, confidence interval; DMARDs, disease-modifying antirheumatic drugs; ELISA, enzyme-linked immunosorbent assay; NSAIDs, nonsteroidal anti-inflammatory drugs; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitors.

Mean TNF-α concentration was 40.0 pg/mL in RA patients with comorbidities (eight studies or 7.7%), 21.8 pg/mL in RA patients without comorbidities (87 studies or 83.7%), and 33.9 pg/mL in RA patients in whom comorbidities were unreported (nine studies or 8.7%; p = 0.08). Mean TNF-α was 35.5 pg/mL in RA patients with a concurrent autoimmune or inflammatory condition (four studies or 3.8%) compared to 22.7 pg/mL in RA patients without a concurrent autoimmune condition (100 studies or 96.2%; p = 0.27).

Mean TNF-α concentration was 18.7 pg/mL in RA patients on RA therapy (67 studies or 64.4%), 32.5 pg/mL in RA patients not on therapy (31 studies or 29.8%), and 25.1 pg/mL in RA patients in whom therapy was unreported (six studies or 5.8%, p = 0.18). Mean TNF-α concentration was 18.3 pg/mL in RA patients on DMARDs (63 studies or 60.6%) and 33.0 pg/mL in RA patients not on DMARDs (41 studies or 39.4%, p = 0.04). Mean TNF-α was 19.3 pg/mL in RA patients on NSAIDs (17 studies or 16.3%) and 24.0 pg/mL in RA patients not on NSAIDs (87 studies or 83.7%, p = 0.61). Mean TNF-α was 12.7 pg/mL in RA patients on corticosteroids (23 studies or 22.1%) and 27.4 pg/mL in RA patients not on corticosteroids (81 studies or 77.9%, p = 0.01). Mean TNF-α was 16.4 pg/mL in RA patients using TNF-α inhibitors (6 studies or 5.8%) and 23.6 pg/mL for RA patients not using TNF-α inhibitors (98 studies or 94.2%, p = 0.55).

Between-study heterogeneity was 99.94%. A sensitivity analysis excluding one study at a time revealed a range of recalculated pooled TNF-α levels between 22.4 and 23.8 pg/mL. Effect sizes of TNF-α (pg/mL) did not change after decreasing the variance to 0.25. Levels increased to 28.05 pg/mL, assuming an I² of 10%, suggesting overall TNF-α level may be slightly higher due to study heterogeneity.

Metaregression

Metaregression showed no association of TNF-α level with type of study, number of cases in each study, presence of additional comorbidities, sex, DAS28-ESR score, ESR or CRP value, disease duration, use of TNF-α inhibitors or corticosteroids, RA therapy overall, age of cases, or Asian study location (Table 2).

Table 2.

Multivariable metaregression of TNF-α levels in rheumatoid arthritis studies.

Variable	Coefficient (95% CI)	p-Value
Type of Study	−1.10 (−2.81 to 0.62)	0.210
Number of cases	−0.02 (−0.08 to 0.04)	0.514
Comorbidity present	2.13 (−2.32 to 6.59)	0.348
Women (%)	0.02 (−0.12 to 0.16)	0.785
DAS28-ESR Score (mean)	1.57 (−0.29 to 3.44)	0.099
ESR	−0.07 (−0.21 to 0.07)	0.323
CRP	0.03 (−0.14 to 0.20)	0.718
Disease duration (years)	0.03 (−0.35 to 0.40)	0.895
TNFi	4.33 (−3.77 to 12.43)	0.295
Corticosteroids	0.63 (−3.06 to 4.32)	0.739
RA therapy	0.95 (−1.80 to 3.70)	0.499
Age (mean)	0.16 (−0.05 to 0.37)	0.131
Asian study	−4.61 (−10.34 to 1.11)	0.114

DAS28-ESR, Disease Activity Score-28 for Rheumatoid Arthritis with ESR; RA, rheumatoid arthritis; TNFi, tumor necrosis factor inhibitors.

TNF-α levels in RA compared to sepsis

We included 70 sepsis studies with available data for circulating TNF-α levels from our previous systematic review and meta-analysis. Pooled estimated mean TNF-α level was numerically higher in sepsis study patients compared to RA study patients (54.7 vs 23.1 pg/mL, respectively; p < 0.0001) in the random-effects model (Figure 3(a)). Metaregression showed no significant difference between TNF-α levels of patients with RA and patients with sepsis after adjustment for age and sex (Supplemental Table 5).¹⁷

Figure 3.

(a) Pooled effect sizes of TNF-α levels showing differences between RA and sepsis depending on the meta-analysis model. (b) Scatter plot values for TNF-α concentrations in studies of patients with RA or sepsis.

A funnel plot examining TNF-α levels for publication bias in RA reports is shown in Supplemental Figure 2. The Egger test showed an estimated slope or B1 of 0.28 with a standard error of 0.86 (p = 0.7403), indicating a lack of small-studies effect. The studies were found to have a moderate risk of bias (Supplemental Table 6).

Discussion

In this systematic review and meta-analysis, the pooled mean circulating TNF-α concentration in RA patients was 23.1 pg/mL in the random-effects model. In subgroup analysis, we found significantly lower TNF-α in RA patients on DMARD therapy compared to those not on DMARD therapy and those on corticosteroids compared to those not on corticosteroids. This was anticipated due to the anti-inflammatory effects of these therapies. This is especially clear for corticosteroids, which have documented broad cytokine suppression, including inhibition of TNF-α, IL-1, and IL-6.¹²⁹ In metaregression, there was no significant association between TNF-α level and study variables. There was a significant difference between TNF-α levels in RA patients in the present study compared to TNF-α levels in sepsis patients from our previous meta-analysis and systematic review.¹⁷ However, the difference did not remain significant after adjusting for age and sex.

Although it appears there is increased TNF-α concentration in sepsis compared to RA, we do not believe the difference is biologically or clinically significant. In addition to the absence of a significant difference in our adjusted analysis, there was considerable overlap in TNF-α levels in RA and sepsis studies (Figure 3(b)). Twenty-five of 104 RA reports showed mean circulating TNF-α concentrations above 58.4 pg/mL, the pooled mean circulating TNF-α level in our systematic review and meta-analysis in sepsis patients.¹⁷ Furthermore, several RA studies reported mean serum TNF-α concentrations substantially higher: three studies reported levels above 100 pg/mL, two studies reported levels above 200 pg/mL, two studies reported levels above 300 pg/mL, one study reported level above 400 pg/mL, one study reported level above 500 pg/mL, and one study reported level above 800 pg/mL.

TNF-α has long been implicated in the pathogenesis of autoimmune and inflammatory diseases. It has proinflammatory effects on the synovium in RA and upregulates the companion proinflammatory cytokine IL-1β.¹³⁰ Early studies demonstrated TNF-α blockade inhibited IL-1 in cultured RA synovial cells and attenuated the severity of inflammation and joint destruction in mouse models.¹³¹ Trials of TNF-α antagonists in patients with RA demonstrate significant reductions in disease activity,^19,132 and drugs that block TNF-α biological activity are approved for the treatment of RA.¹³³ Despite the success of TNF-α blockade in RA, trials of myriad anti-cytokine and anti-inflammatory therapies for the treatment of sepsis (including specific TNF-α blockade) have failed consistently.^15,134,135

There are good reasons to believe TNF-α concentration comprises the best available marker for inflammation, and this explains the large number of clinical trials exploring TNF-α suppression in diseases thought to be mediated by inflammation. The gold standard for determining a role for TNF-α in a disease is to specifically block TNF-α bioactivity and assess for effect on disease severity. The fact that TNF-α blockade in RA moderates disease activity, yet TNF-α blockade does not moderate sepsis, provides powerful evidence that inflammation has a pivotal role in RA pathogenesis but not in sepsis pathogenesis. The results shown in this report provide additional support for the concept that TNF-α does not contribute to sepsis. Commensurable TNF-α circulating levels in RA and sepsis weigh against a causal role for inflammation in sepsis. The high acute mortality in sepsis differs markedly from the clinical course of RA, and this observation weakens any link between TNF-α and sepsis mortality.

The likely explanation for the efficacy of TNF-α blockade in RA but not sepsis is the inadequacy of the hyperinflammation concept of sepsis pathogenesis. In previous publications, we provided strong reasons for believing that circulating TNF-α and other cytokines, such as IL-6 and IL-1β, serve little, if any, causative role in sepsis pathogenesis.^15,16,136 In the current report, we found a relatively small absolute difference in TNF-α levels in RA compared to sepsis, extensive overlap in TNF-α between the two conditions, and a non-significant difference in adjusted analysis (Figure 3(b)). Comparable circulating TNF-α concentrations between RA and sepsis are of interest given the absence of acute organ malfunction or death in RA attributable to a “TNF-α storm.” Levels of TNF-α in RA provide empirical quantitative data that support our theoretical analysis showing TNF-α concentrations in sepsis are inadequate (by several orders of magnitude) to cause organ malfunction or mortality.¹⁵

Limitations

This study has several limitations. There was significant heterogeneity between studies as demonstrated by a high I² statistic. Possible etiologies for heterogeneity include variability in study design, TNF-α measurement technology, timing of TNF-α measurement during RA, underlying RA severity and duration of illness, comorbidities, and use of anti-RA therapy or other interventions that may bias results to misrepresent true TNF-α concentrations in RA. Inaccuracies in TNF-α measurement or reporting may also have occurred, including erroneous reporting of TNF-α unit values as discussed in the methods section. In addition, TNF-α levels in RA may relate to unknown confounding covariates that cannot be adjusted for using available source reports. Future studies may use narrower inclusion criteria, such as including only certain study designs, TNF-α measurement technology, or RA severity or treatment status, to minimize heterogeneity.

Comparison between pooled mean TNF-α levels in RA and sepsis is limited by different patient populations and study characteristics.

Conclusion

The pooled mean circulating TNF-α level was 23.1 pg/mL in patients with RA using a random-effects model. There was no significant difference between the pooled mean TNF-α level in patients with RA compared to patients with sepsis, determined in our previous systematic review and meta-analysis, after adjusting for age and sex.¹⁷ These results suggest that for TNF-α concentrations in sepsis, the answer to the question, “Is that a lot?” is “No.” Despite comparable TNF-α levels in RA and sepsis, human trials have shown benefit for TNF-α blockade in patients with RA and consistent failure in patients with sepsis. It is likely TNF-α plays no significant causative role in sepsis pathogenesis, and thus it is reasonable to anticipate interventions designed to suppress TNF-α as a sepsis treatment will continue to fail.

Supplemental Material

sj-docx-1-tai-10.1177_20499361251368006 – Supplemental material for Circulating TNF-α levels in rheumatoid arthritis: a systematic review and meta-analysis and comparison to TNF-α levels in sepsis

Supplemental material, sj-docx-1-tai-10.1177_20499361251368006 for Circulating TNF-α levels in rheumatoid arthritis: a systematic review and meta-analysis and comparison to TNF-α levels in sepsis by Sias Scherger, Andrés F. Henao-Martinez, Carlos Franco-Paredes, Binh T. Ngo, Alyssa Grimshaw, Ranjit Sah, Sangam Shah, Stefan Sillau, Alfonso G. Bastias, Michaele Francesco Corbisiero, Hannah M. Kyllo, Jordan Stellern and Leland Shapiro in Therapeutic Advances in Infectious Disease

Footnotes

Acknowledgements

Vesean Daniels, Harvey Cushing/John Hay Whitney Medical Library, Yale University, New Haven, CT, USA.

Declarations

ORCID iDs

Sias Scherger

Andrés F. Henao-Martinez

Michaele Francesco Corbisiero

Supplemental material

Supplemental material for this article is available online.

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