A Systematic Review and Meta-Analysis to Inform Cancer Screening Guidelines in Idiopathic Inflammatory Myopathies

Alexander G. S. Oldroyd; Andrew B. Allard; Jeffrey P. Callen; Hector Chinoy; Lorinda Chung; David Fiorentino; Michael D. George; Patrick Gordon; Kate Kolstad; Drew J. B. Kurtzman; Pedro M. Machado; Neil J. McHugh; Anna Postolova; Albert Selva-O'Callaghan; Jens Schmidt; Sarah Tansley; Ruth Ann Vleugels; Victoria P. Werth; Rohit Aggarwal

Disclosures

Rheumatology. 2021;60(6):2615-2628. 

In This Article

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.

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