A systematic review and meta-analysis to inform cancer screening guidelines in idiopathic inflammatory myopathies

Abstract

Objectives

To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to cancer screening.

Methods

A systematic literature search was carried out on Medline, Embase and Scopus. Cancer risk within the IIM population (i.e. not compared with the general population) was expressed as risk ratios (RR) for binary variables and weighted mean differences (WMD) for continuous variables. Evidence relating to cancer screening practices in the IIMs were synthesized via narrative review.

Results

Sixty-nine studies were included in the meta-analysis. DM subtype (RR 2.21), older age (WMD 11.19), male sex (RR 1.53), dysphagia (RR 2.09), cutaneous ulceration (RR 2.73) and anti-transcriptional intermediary factor-1 gamma positivity (RR 4.66) were identified as being associated with significantly increased risk of cancer. PM (RR 0.49) and clinically amyopathic DM (RR 0.44) subtypes, Raynaud’s phenomenon (RR 0.61), interstitial lung disease (RR 0.49), very high serum creatine kinase (WMD −1189.96) or lactate dehydrogenase (WMD −336.52) levels, and anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity were identified as being associated with significantly reduced risk of cancer. Nine studies relating to IIM-specific cancer screening were included. CT scanning of the thorax, abdomen and pelvis appeared to be effective in identifying underlying asymptomatic cancers.

Conclusion

Cancer risk factors should be evaluated in patients with IIM for risk stratification. Screening evidence is limited but CT scanning could be useful. Prospective studies and consensus guidelines are needed to establish cancer screening strategies in IIM patients.

Introduction

Idiopathic inflammatory myopathies (IIMs) are chronic multisystem autoimmune conditions that may cause muscle inflammation (myositis), skin manifestations and interstitial lung disease (ILD) [1, 2]. Adult-onset IIMs are associated with increased risk of cancer. A recent meta-analysis of such studies reported a standardized incidence ratio of 4.66 for DM and 1.75 for PM [3]. The generally accepted definition of cancer associated myositis (CAM) is malignancy within 3 years of IIM onset. Cancer remains the leading cause of death for adults with IIM [4–6].

Around one in four patients are diagnosed with cancer within 3 years before or after IIM onset [4]; however, risk varies according to the presence/absence of certain factors [7]. Unfortunately, the data regarding risk factors are largely derived from retrospective studies with small populations, thus limiting the ability to form robust conclusions and extrapolate to the wider population.

Meta-analysis of existing evidence could synthesize results across studies and identify factors associated with cancer in IIM populations, thus potentially accounting for biases, such as publication bias and outlier studies. Further, assimilation of evidence relating to cancer screening specific to CAM could provide an evidence base informing clinical screening practices and facilitate the formulation of cancer screening guidelines.

The International Myositis Assessment and Clinical Studies Group (IMACS), the largest international group for scientific studies in myositis, began a special interest group to develop evidence-based cancer screening guidelines for newly diagnosed IIM patients. This meta-analysis forms an important component in guideline formation. Therefore, the overall aim of this study is to identify risk factors associated with CAM using meta-analysis, and to systematically review existing evidence relating to CAM screening approaches.

Methods

We performed a systematic review of factors associated with cancer in IIM populations and screening practices. Evidence pertaining to factors associated with cancer were assimilated via meta-analysis. Results of studies relating to cancer screening in IIM populations were assimilated into a narrative review. Study selection, data extraction, quality assessment, data synthesis and analysis were all carried out in adherence to PRISMA guidelines (for PRISMA checklist see Supplementary Material, available at Rheumatology online) [8].

Data sources

A systematic literature search was carried out on Medline via PubMed, Embase via OVID and Scopus. The following were used to identify appropriate studies: ‘myositis’, ‘neoplasm’, ‘screening’. Full-length peer reviewed articles published in English language before 8 January 2020 were included. Case reports, letters and conference abstracts were excluded. References of each identified study were also examined for further appropriate studies.

Study selection

Studies were included in the risk factor meta-analysis if they provided data on at least one risk factor, included at least 10 IIM study subjects, and provided data on an IIM control group. It is important to note that risk factors were assessed in comparison to each study’s wider IIM population, not the general healthy population. Eligible IIM subtypes included DM, PM, anti-synthetase syndrome (ASS), immune-mediated necrotizing myopathy (IMNM) and clinically amyopathic DM (CADM). Data relating to inclusion body myositis were excluded due to the relationship with cancer being distinct from that of other IIM subtypes [4]. Only the study with the largest cohort was included where repeated studies utilized the same cohort data, where identifiable.

For the review of screening practices, studies that assessed at least one cancer screening approach/modality in an IIM population were included.

Data extraction

Each eligible article was independently reviewed by two reviewers (A.O., M.D.G., D.K., S.T., A.A., A.P. and K.K.). The title and study abstracts were reviewed to assess eligibility/ineligibility. Preliminary full text reviews were carried out where eligibility/ineligibility could not be decided using the title and abstract alone. Full text review of each eligible article was carried out by a single reviewer. Extracted data included study type, population studied, sample size, risk factors evaluated, number of cases (i.e. those with risk factors), controls (i.e. those without risk factors), and number of cases and controls diagnosed with cancer (excluding non-melanotic skin cancers). Available data (e.g. mean, s.d., median, range) on continuous risk factors, such as age, in those with/without cancer were also collected. A second reviewer reviewed selected studies to ensure accuracy of data extraction. The quality of studies and bias assessment was carried out using the GRADE system developed by the Scottish Intercollegiate Guidelines Network, where each study was given a quality assessment of either very low, low, moderate or high [9]. Studies were excluded if they were deemed to be of low or very low quality or subject to a high risk of bias according to the GRADE system. Agreement of both reviewers was required to remove a study according to bias. The decision of study inclusion/exclusion was made by a third reviewer in the case of differing assessments.

Data synthesis and analysis

Meta-analysis was carried out for each risk factor where data from at least two eligible studies were available. Investigated factors included IIM subtypes, demographics, clinical features, laboratory parameters and autoantibodies. The denominator used in cancer risk estimation for each factor was the remaining IIM population of each study, not the general population. The cancer risk associated with individual ASS-related autoantibodies (anti-Jo1, anti-PL7, anti-PL12, anti-EJ, anti-OJ, anti-KS) was considered. Subsequently, the risk associated with the presence of any ASS-related autoantibody was calculated by combining studies that compared risk against non-ASS IIM controls. Risk ratios (RRs) were calculated for binary variables (e.g. presence of ILD). The weighted mean difference (WMD) for each continuous variable (e.g. age) was calculated by comparing means and s.d.s. The mean (s.d.) was calculated from studies that reported only median and range using methods described by Hozo et al. [10].

The small number of studies that reported the utility of cancer screening approaches in IIM populations precluded a meta-analysis, therefore a narrative review was carried out.

Heterogeneity and study sample size analysis

Heterogeneity was assessed using the standard chi-squared test and I² statistic. Further analysis was carried out for factors with very high levels of heterogeneity (I² >75%). Influence analysis (‘leave-one-out’) was carried out to identify outlier studies, that is those with extreme effect sizes, and thus substantially contributing to heterogeneity. A study was considered an outlier if it fulfilled the cut-off criteria proposed by Viechtbauer et al. [11].

Egger’s test was used to assess the influence of study cohort size on calculated effect sizes [12]. ‘Trim and fill’ was used to calculate adjusted effect sizes for factors with significant (<0.05) Egger’s test P-values [13].

All analysis was carried out using the statistical programme R [14], and the meta [15] and metaphor [16] packages.

Results

A total of 7030 articles were initially identified via the literature search and 141 were reviewed for eligibility following removal of ineligible papers, duplicates, case reports and reviews (Fig. 1). Sixty-seven studies were included in the risk factor meta-analysis (Fig. 1) and nine in the screening narrative review (two studies were included in both the meta-analysis and systematic review). Table 1 displays the summary RRs and WMDs calculated for each risk factor. See Supplementary Material for forest plots for each risk factor and further details of each study (Supplementary Table 1, available at Rheumatology online).

IIM subtypes

DM was significantly associated with a higher risk of cancer compared with other IIM subtypes [17–40]. PM [17–28, 30, 31, 33–40] and CADM [28, 35, 41] were found to be associated with significantly lower risk for cancer compared with remaining IIM subtypes. ASS subtype was a non-significant factor; however, data from only two eligible studies were available [21, 42]. Insufficient data were available to perform meta-analysis on data relating to IMNM.

Clinical factors including demographics and laboratory values

Demographics

Older age at time of IIM onset was found to be significantly associated with increased risk of cancer [21, 22, 28, 29, 32, 33, 36, 39, 42–54]. The mean age of IIM onset in cancer cases was 59 years, compared with 49 years in the non-cancer cases. Male sex was found to be significantly associated with higher risk of cancer, compared with female sex [17, 18, 21, 22, 25–30, 32–34, 36, 38, 39, 41–59].

Clinical risk factors

Sufficient data were available to quantify the cancer risks associated with dysphagia, cutaneous ulceration, Raynaud’s phenomenon and ILD. Dysphagia, which was typically not objectively defined across the majority of studies, was significantly associated with higher risk of cancer [22, 25, 26, 29, 32, 33, 39, 43, 46, 47, 49, 56, 59, 60]. Cutaneous ulceration was also significantly associated with higher risk of cancer [45, 46, 49, 50, 53]. Analysis revealed that the presence of Raynaud’s phenomenon was associated with a significantly lower risk of cancer [22, 25, 26, 29, 30, 39, 41, 45, 46, 50, 59]. The presence of ILD, which was typically diagnosed via CT scanning, was also associated with a significantly lower risk of cancer [22, 26, 28–30, 32, 33, 35, 39, 43, 45, 46, 56, 59].

Laboratory values

Lower creatine kinase (CK) [22, 27, 29, 32, 33, 38, 39, 43, 46, 53] values were significantly associated with increased cancer risk, therefore, conversely, very high values were associated with lower risk of cancer. It is important to note, however, that the mean CK level in cancer cases (2402 IU/l) was still raised compared with normal values, but lower than the non-cancer group (3557 IU/l). Similarly, lower lactate dehydrogenase (LDH) [22, 32, 33, 38, 39, 46, 53] values (mean LDH 766 U/l) were found to be associated with increased cancer risk as compared with higher LDH values (mean LDH 1078 U/l). Both alanine transaminase (ALT) [29, 38, 53] and ESR [22, 29, 33, 38, 43, 45] levels were found to be non-significant factors, and insufficient data were available for aspartate aminotransferase and aldolase.

Autoantibodies

Anti-transcriptional intermediary factor-1 gamma (anti-TIF1γ) positivity was significantly associated with increased cancer risk [21, 31, 37, 41, 44, 48, 58, 60–71]. Anti-nuclear matrix protein 2 (anti-NXP2) positivity was a non-significant factor [21, 37, 61, 62, 68, 71–76]. Large proportions of the control cohorts in studies of anti-NXP2-positive cohorts were comprised of anti-TIF1γ-positive cases. We repeated meta-analysis after removing anti-TIF1γ-positive cases. The RR of anti-NXP2 using data from six studies with anti-TIF1γ cases excluded was 1.47 [95% confidence interval (CI): 0.57, 3.80; I² 0.00%], again indicating that positivity for anti-NXP2 is a non-significant factor for cancer relative to other autoantibody subtypes [21, 37, 62, 68, 71, 73].

Analysis was carried out for each individual ASS-related autoantibody. Anti-Jo-1 [21, 22, 25, 26, 29, 33, 46, 59, 62, 71, 77] and anti-EJ [21, 62, 71, 78, 79] were significantly associated with reduced cancer risk. Positivity for anti-PL7 [21, 62, 71, 78, 79], anti-PL12 [21, 62, 71, 78, 79], anti-OJ [21, 71, 78, 79] and anti-KS [71, 79] were non-significant factors, although limited by small number of studies. Analysis revealed that the presence of any ASS-related autoantibody was significantly associated with lower risk of cancer [21, 22, 25, 26, 29, 33, 59, 62, 70, 71].

Positivity for other autoantibodies, including anti-3-hydroxy 3-methylutaryl coenzyme A reductase (anti-HMGCR) [21, 62, 71, 80, 81], anti-signal recognition particle (anti-SRP) [62, 71, 80], anti-small ubiquitin-like modifier-1 activating enzyme (anti-SAE1) [21, 62, 71], anti-melanoma differentiation-associated gene 5 (anti-MDA5) [21, 44, 48, 62, 71] or anti-Mi2 [21, 41, 58, 62, 64, 71], were identified as non-significant factors for cancer. Both myositis specific autoantibody (MSA) negativity [21, 30, 45, 62, 71] and ANA positivity [22, 26, 28, 30, 39, 41, 43, 46, 50, 53, 54, 56, 82] were non-significant factors.

Heterogeneity and publication bias

Table 1 displays the standard chi-squared test results and I² statistic for heterogeneity of each analysed factor. Influence analysis aimed to identify outlier studies for risk factors with very high (>75%) heterogeneity. One study each fulfilled the outlier criteria for CK [53], ESR [45] and ALT [53]. Adjusted WMD after removal of data from outlier publication was calculated and did not change overall relationships (Supplementary Table 2, available at Rheumatology online).

Significant publication bias was observed with ‘any ASS-antibody’. Adjusted RR following ‘trim and fill’ analysis with six added studies was 0.46 (95% CI: 0.23, 0.93).

Cancer screening utility review

Nine studies [40, 45, 83–89] relating to utility of cancer screening approaches in IIM populations were identified. Table 2 displays the details of each study. A total of 90 cancers were identified via screening across 1033 patients. Studies were carried out across a number of countries, including the USA, Canada, Taiwan, China, France and Spain, and widely ranging intervals between IIM onset/diagnosis and screening were reported. All but one study was retrospective. Study population sizes ranged between 14 and 400. A wide variety of cancers were diagnosed, including but not limited to breast cancer, squamous cell carcinoma, multiple myeloma, ovarian cancer, lymphoma, lung cancer and oesophageal cancer.

The utility of ‘blind screening’ (i.e. investigations carried out in the absence of target symptoms) was reported by Leatham et al. [85] and Sparsa et al. [45]. Leatham et al. identified 17 out of 48 cancer patients diagnosed with cancer via blind screening modalities after DM onset. CT scanning of the thorax, abdomen or pelvis detected the most cancer diagnoses (6/17, 38%), followed by mammography (3/17, 18%). Sparsa et al. reported the identification of 30 cancers via 122 investigations. Thirty-five investigations were ‘directed’ (i.e. initiated due to the presence of target symptoms) and resulted in the identification of 19 (54%) cancers. In contrast, 87 investigations were blind and identified 11 (13%) cancers. Again, CT scanning of the thorax, abdomen and pelvis was the single investigation that detected the most cancers (5/18, 28%).

The utility of ¹⁸F-FDG PET/CT was reported by Maliha et al. [84] and Selva-O’Callaghan et al. [88]. Maliha et al. reported that fluorodeoxyglucose (¹⁸F-FDG) PET/CT scans revealed no further cancer diagnoses and actually lead to more biopsies, compared with ‘conventional’ screening (see Table 2 for details). Similarly, Selva-O’Callaghan reported that single ¹⁸F-FDG PET/CT scans were comparable to a large number of conventional screening investigations, which included complete physical examination, laboratory tests (complete blood count and serum chemistry panel), thoraco-abdominal CT scan, tumour markers [carbohydrate antigen-125 (CA125), CA19-9, carcinoembryonic antigen (CEA), prostate-specific antigen], gynaecological examination, ovarian ultrasonography and mammography.

The screening utility of CA125 was demonstrated by Amoura et al. [89] and Whitmore et al. [87]. Amoura et al. demonstrated that increased levels were significantly associated with subsequent cancer diagnoses (OR 29.7; 95% CI: 8.2, 106.6; P-value <0.0001). Whitmore et al. also demonstrated the utility of normal values—no study participant with normal CA125 levels was subsequently diagnosed with cancer during the study period. In contrast, Lim et al. concluded that CA125 testing was not useful for detection of cancer [40]. Eighteen participants had raised CA125 levels and only one (6%) was subsequently diagnosed with cancer. Additionally, 53 participants had normal CA125 levels and two (4%) were diagnosed with cancer.

Both Amoura et al. [89] and Lim et al. [40] reported the screening utility of CEA, CA15-3 and CA19-9 (Table 2). Raised CEA or CA15-3 levels were not associated with cancer in each study. Raised CA19-9 levels were significantly associated with cancer in the study by Amoura et al.; 11 cases had raised levels and three subsequently developed cancer (OR 4.5; 95% CI: 1.00, 18.7; P-value 0.018). Raised CA19-9 levels were not found to be associated with cancer in the study by Lim et al. however. Of note, Amoura et al. reported that three cases had raised levels of both CA19-9 and CA125 and all of these were subsequently diagnosed with cancer (OR 86.3; 95% CI: 4, 1832; P-value <0.0001). Lim et al. also reported no association between raised AFP levels and cancer. Interestingly, Lim et al. reported an association between CA15-3 levels and the development of ILD; eight (89%) of the nine patients with increased CA15-3 levels were diagnosed with ILD.

Discussion

This meta-analysis has quantified the relationship between 30 clinical factors and the risk of cancer in IIM patients. Fifteen factors significantly associated with cancer risk were identified. Existing evidence relating to the utility of cancer screening in IIM populations was also reviewed, providing information useful for the future formation of cancer screening guidelines.

DM, increasing age, male sex, dysphagia, cutaneous ulceration and the presence of anti-TIF1γ were all associated with increased cancer risk. The magnitude of risk of cancer was greatest for those positive for anti-TIF1γ, with a fourfold increased risk. Very high LDH or CK values were associated with reduced cancer risk.

PM and CADM subtypes were associated with lower risk of cancer compared with other subtypes. However, the risk of cancer in PM and CADM cases may be reduced, but the risk is still raised compared with the general population, as previously identified [3].

ASS subtype was a non-significant factor for cancer; however, this was based on data from only two studies. The presence of ILD or any ASS-related antibody, in particular anti-Jo1 and anti-EJ, were significantly associated with lower cancer risk. ASS is characterized by ILD and the presence of any ASS-related antibody, therefore it may be concluded that ASS patients are at significantly lower cancer risk compared with other IIM subtypes.

Insufficient evidence was available to include IMNM subtype in the meta-analysis. However, meta-analysis was possible for anti-SRP and anti-HMGCR, both IMNM-specific autoantibodies. Positivity for either anti-SRP or anti-HMGCR were non-significant factors for cancer. Additionally, very high CK levels, which are also typically observed in IMNM cases, were associated with reduced cancer risk. A small number of studies have reported increased risk of cancer in IMNM patients compared with the general population; however, the risk may be dependent on autoantibody status, as reported by Allenbach et al. [80], where anti-HMGCR positivity was associated with increased cancer risk and anti-SRP positivity was not. An increased cancer risk associated with anti-HMGCR positivity compared with the general population was, however, not found by Tiniakou et al. [90]. Overall, the relationship between IMNM and cancer remains unclear, and further research in larger cohorts is warranted.

Anti-NXP2 positivity was not associated with cancer in this meta-analysis even after removal of anti-TIF1γ-positive cases, where possible. Previous studies have, however, highlighted the increased risk of anti-NXP2 positivity compared with the general population, for example Yang et al. reported a cancer risk standardized incidence ratio of 8.14 compared with the general population [21]. It is perhaps, therefore, still appropriate to consider anti-NXP2 positivity a cancer risk factor when considering comparison to the general population. Further research to fully delineate the cancer risk associated with anti-NXP2 positivity is warranted.

Few previous studies have investigated the utility of cancer screening approaches in IIM populations; however, a number of conclusions can be drawn.

Firstly, imaging of internal organs via CT scanning of the thorax, abdomen and pelvis appeared to yield a high proportion of cancers. CT scanning is a readily available low-cost investigation and therefore represents a potentially useful method of screening.

Secondly, CA125 levels may potentially be useful in stratifying patients’ ovarian cancer risk. It is important to note, however, that the evidence is overall weak, with only three studies reporting relevant results.

Thirdly, neither of the two included studies demonstrated that ¹⁸F-FDG PET/CT scanning leads to a higher yield of cancer diagnosis [84, 88]. The study by Selva-O’Callaghan et al., however, indicated that ¹⁸F-FDG PET/CT scanning was comparable to a wide panel of extensive screening investigations in ability to detect cancers. This indicates that a single ¹⁸F-FDG PET/CT scan may potentially negate the need for numerous investigations. It is important to note the small population sizes in the studies by Maliha et al. [84] and Selva-O’Callaghan et al. [88] and non-stratification according to the presence of risk factors, thus precluding extrapolation of utility of ¹⁸F-FDG PET/CT in IIM patients with risk factors. The higher number of biopsies performed following ¹⁸F-FDG PET/CT without subsequent cancer diagnoses, as reported by Maliha et al., is also a potential disadvantage. ¹⁸F-FDG PET/CT can provide potentially useful IIM-specific clinical information relating to ILD and myositis [91]. Further, a single ¹⁸F-FDG PET/CT scan can result in lower out of pocket expenses for patients (US $127 less), compared with a broad panel of screening investigations (i.e. CT, tumour markers, faecal occult blood, mammography, ovarian ultrasonography) [92]. However, a small but potentially important radiation exposure of 25 mSv is associated with an ¹⁸F-FDG PET/CT scan, compared with 14–19 mSv with a standard whole-body CT scan [93]. ¹⁸F-FDG PET/CT may therefore represent a cost-effective single investigation that can identify underlying malignancy and detect ILD and myositis, thus removing the need for further multiple screening investigations. Further evidence is, however, required to fully delineate the role of ¹⁸F-FDG PET/CT scanning as a screening strategy for cancer in IIM patients.

As previously mentioned, all results and findings in this study pertain only in comparison to IIM patients, not the general population. Future research and meta-analysis may consider delineating the cancer risk of appropriate factors in comparison to the general population.

One major potential limitation to this study is the varying MSA detection methods employed by different studies. This introduces the risk of varying accuracy of MSA detection, thus affecting the calculated effect sizes. Further, substantial heterogeneity potentially limits the clinical translation of variables studied. Publication bias was observed with any ASS-related antibody, thus highlighting potential inaccuracy of calculated effect sizes. Recent advances in understanding raise the possibility that PM cases may actually represent other subtypes, such as IMNM or other neuromuscular disorders [94–96], thus potentially limiting the accuracy of the estimated cancer risk associated with PM. Calculation of the cancer risk associated with connective tissue disease-associated IIM (overlap IIM) was not possible due to varying classification. A number of potential risk factors such as ethnicity, arthralgia, arthritis and fever were not included in this meta-analysis due to unavailability of objective data. No studies addressed whether or not repeated cancer screening is beneficial in identifying cancer; evidence on this important topic will impact screening practices, especially in patients where no cancer was diagnosed via initial screening. The potential interaction of the presence of multiple risk factors and their impact upon stratification of cancer risk in IIM has never been evaluated. The small number of studies that report the utility of cancer screening investigations highlights the need for further research in this area.

Conclusion

This meta-analysis has quantified the risk of cancer associated with a large number of clinical risk factors and MSAs, which can inform cancer screening practices for IIM patients. In addition, the systematic review of available evidence related to utility of cancer screening investigations, although limited, can also inform clinical decisions and aid guideline development in this area. Overall, these results can inform the development of cancer screening guidelines, thus potentially leading to earlier cancer diagnosis and improved patient outcomes.

Acknowledgements

This study was developed and conducted under the International Myositis Assessment and Clinical Studies Group (IMACS). R.A. conceived and designed the study. A.O., M.D.G., D.K., S.T., A.A., A.P. and K.K. carried out the literature review and data extraction. A.O. carried out all data analysis. A.O. led manuscript preparation. All authors reviewed results, critically appraised the manuscript and approved the final version.

Funding: This report includes independent research supported by the National Institute for Health Research Biomedical Research Centre Funding Scheme. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research or the Department of Health.

This work was supported by funding from Myositis UK (to A.O); Versus Arthritis (Award Number: 21993 to A.O.); the National Institute for Health Research Manchester Biomedical Research Centre (to A.O. and H.C.); the National Institute for Health Research University College London Hospitals Biomedical Research Centre (to P.M.M.) and Bath Institute of Rheumatic Diseases (to S.T.).

Disclosure statement: R.A. served as a consultant for Kezar, Csl Behring, AstraZeneca, Octapharma, BMS, Pfizer, Janssen, Mallinckrodt, Alexion, Q32, Argenx, Boehringer-Ingelheim, Corbus and EMD-Serono; and received research funding from Pfizer, BMS, Genentech, Kezar, Csl Behring and Mallinckrodt. L.C. served on an advisory board and received grant funding from Boerhinger Ingelheim; served on an advisory board for Eicos Sciences; served on an advisory board for Bristol-Myers Squibb; received consulting fees for Mitsubishi Tanabe; and serves on a data safety monitoring board for Reata. M.D.G. received a research grant from Bristol-Myers Squibb for unrelated work; and consulting fees from Dysimmune Diseases Foundation. P.M.M. received consulting/speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, outside the submitted work. R.A.V. received a research grant from Pfizer. H.C. received research grants, travel grants, consultancy or speaker honoraria from AbbVie, Amgen, BMS, Biogen, Janssen, Lilly, Novartis and UCB. V.P.W. served as a consultant for Kezar, CSL Behring, AstraZeneca, Octapharma, Pfizer, Janssen, Neovacs and Idera; and received research funding from Pfizer, CSL Behring and Corbus.

Data availability statement

There are no new data associated with this article.

Supplementary data

Supplementary data are available at Rheumatology online.

References