Page 191 - 2020_11-Haematologica-web

Letters to the Editor
Peripheral neuropathy and monoclonal gammopathy of undetermined significance: a population-based study including 15,351 cases and 58,619 matched controls
Monoclonal gammopathy of undetermined signifi- cance (MGUS) is a common benign precursor condition of multiple myeloma (MM) and related disorders.1,2 MGUS is considered asymptomatic but has been shown to be associated with peripheral neuropathy (PN).3 However, the literature is unclear regarding the preva- lence, clinical implications, and even the existence of MGUS-associated PN.4 We therefore conducted a large population-based study of MGUS and PN. We found PN to be truly associated with MGUS and under-recognized in clinical practice. Furthermore, PN was associated with a 2.9-fold risk of a light-chain amyloidosis (AL).
We included individuals with MGUS diagnosed in Sweden between 1986-2013, as has been described pre- viously.5 Four controls that were alive and free of lym- phoproliferative disease were matched to each case on the day of MGUS diagnosis by sex, year of birth, and county of residence. Data from Swedish national reg- istries were cross-linked to participants using a unique identification number.
The primary endpoint was PN as recorded in the Swedish Patient Registry using International Classification of Diseases (ICD) codes by Swedish physi- cians recording their clinical diagnoses. However, under- lying symptoms or diagnostic testing leading to PN diag- nosis were not available. Acute inflammatory neu- ropathies and critical care neuropathy were excluded. Symptomatic codes were included but were excluded in a sensitivity analysis. We assessed the prevalence of PN in the full cohort and followed those who did not have PN at inclusion until PN or censoring at death as recorded in the Swedish Cause of Death Registry, lymphoprolifer- ative disease as recorded in the Swedish Cancer Registry, or end of follow-up. We then estimated hazard ratios (HR) using Cox proportional hazard regression adjusting
for age, sex, and year of inclusion. PN is common in the general population but is often undetected.6 Individuals with MGUS, who are under medical surveillance, might therefore have more diagnoses of a PN that might other- wise have stayed subclinical in the control population. To mitigate this bias, we also stratified the cohort by dia- betes mellitus (DM) and repeated the analysis. DM patients are under regular medical surveillance, similar to that of patients with MGUS. Furthermore, PN is a well- known feature of DM, and DM patients often undergo PN screening during follow-up, presenting a more appro- priate comparison group.
In a secondary analysis, we assessed the association of PN and MGUS progression and death. We included all participants with MGUS and considered PN as the expo- sure. We then followed them until death or the diagnosis of MM, Waldenström’s macroglobulinemia (WM), and AL in four separate analyses while censoring at the other endpoints or loss to follow-up. In order to prevent immortal time bias in those participants who developed PN after MGUS diagnosis, we included PN as a time- dependent covariate in a Cox proportional hazard regres- sion model. The models were adjusted for age, sex, and year of MGUS diagnosis, as well as for DM when assess- ing risk of death.
A total of 15,351 participants with MGUS and 58,619 matched controls were included in the study. The preva- lence of PN was higher in participants with MGUS than controls (6.5% vs. 2.8%) (Table 1). The reported preva- lence of PN varies widely but more recent observational studies estimate the prevalence at 15-20%.7 Therefore, these findings, based on clinical diagnoses of PN, indicate under-recognition of PN during the clinical care of indi- viduals with MGUS.
Individuals with MGUS had 2.7-fold risk of PN com- pared to matched controls (HR=2.7; 95% confidence interval [95%CI]: 2.4-3.1; P<0.001). After stratification for DM, we found MGUS and DM to be associated with higher risk of PN as compared to controls without MGUS and DM (MGUS alone: HR=3.0; 95%CI: 2.6-3.4; P<0.001 and DM alone: HR=3.6; 95%CI: 3.2-4.2; P<0.001).
Table 1. Baseline characteristics of study participants in the original cohort and after additional stratification for diabetes mellitus (DM) as well as results of a Cox proportional hazard regression model of risk of peripheral neuropathy (PN) for each group.
Original cohort
MGUS Control
15,351 58,619
73 72
18-104
51% 51%
18-101
After DM stratification
N
Median age (years) Age range (years) %male
N by year of inclusion
1986-1995 1996-2005 2006-2013
PN
before MGUS/matching (% of PN)
Median follow-up (years)
Risk of PN in HR (95% CI)1
MGUS alone
12,818
72 18-104
DM alone
7,953
74 26-97
MGUS+DM
2,533
74 26-95
Control
50,666
72 18-101
50% 58% 58.1 50%
22%
33%
45%
996 (6.5%) 549 (55%)
4.0
22%
33%
45%
1,644 (2.8%) 770 (47%)
6.1
22%
33%
45%
681 (5.3%) 376 (55%)
23%
35%
42%
620 (7.8%) 310 (50%)
22%
31%
47%
315 (12.4%) 173 (55%)
21%
33%
46%
1024 (2.0%) 460 (45%)
4.1
6.1
3.7
6.1
2.7 (2.4-3.1)***
Reference
-
-
-
-
-
-
3.0(2.6-3.4)***
0.8 (0.7-1.0)*
3.6(3.2-4.2)*** 7.5(6.3-9.1)***
Reference 2.1 (1.7-2.5)***
Reference
0.3 (0.2-0.3)***
-
-
1Adjusted for sex, age, and year of inclusion. *P<0.05, ***P<0.001, MGUS: monoclonal gammopathy of undetermined significance; HR: hazard ratio, 95% CI: 95% confidence interval; N: number.
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