Discussion
Elevated levels of sFLC have been found in a variety of ADs, including
systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome,
ankylosing spondylitis, psoriatic arthritis, vasculitis although many
studies included a small number of patients [5, 18, 19].
In these ADs, sFLC correlated strongly with inflammatory mediators,
activity and severity index demonstrating their potential for predicting
disease activity [19, 20].
Few studies have quantified the FLC in SSc and only one in the serum
[10]. Bosello et al found elevated k-sFLC vs HC that correlated with
restrictive lung disease, disease activity and inflammatory biomarkers
such as ESR, CRP and interleukin-6 (IL-6) [6]. IL-6 is produced by
activated B cells and the authors suggest that sFLC may play a role in
the pathogenetic mechanisms of SSc. As multifunctional cytokine, IL-6
plays a well-recognized role in inflammatory, immunoregulatory and
haemopoietic responses. Thanks to a trans-signaling mechanism mediated
by its soluble receptor, IL-6 may orchestrate a wide range of
inflammatory-immune properties [21-23]. Among biological properties
of IL-6, the stimulation of collagen synthesis by dermal fibroblasts is
well recognized [24].
In fact, high levels of IL-6 are found in the skin and serum of SSc
patients connecting the role of this cytokine in the onset of
inflammation and fibrosis through the activation of B cell and the
subsequent production of sFLC [25]. Moreover, Lanteri et al,
analyzing 134 SSc patients found a correlation between sFLC and BAFF
levels [10] The BAFF family, play a pivotal fundamental role in B
cell development, maturation, and survival and it is found higher in the
skin and serum and of SSc patients [25].
Serum FLC is a marker of polyclonal activation and here we showed that
in our patients both serum free k and λ and k + λ sum correlate with ESR
and CRP. In addition, a linear correlation was found between serum free
k with DAI and DSS. In addition, when specific cut-off values for normal
range of sFLC were considered, SSc patients with abnormal serum free k
and k+ λ-sum showed a positive correlation with DAI and DSS.
Thus, supporting the role of B cell activation in the pathophysiology of
SSc, an overproduction of FLCs may occur because of chronic immune
stimulation. This fit well with the proposed role of FLC as a biomarker
of B cell activity as suggested in many studies on Ads [5].
To our knowledge, this is the first study that includes the evaluation
also of urinary FLC in patients with SSc.
The main result of our study is that urinary FLC levels were found to be
elevated in comparison to the HC. Higher urine free k levels, k+ λ sum,
k/λ ratio>1.80 were found in SSc patients, while urine λ
levels were comparable to HC.
Since in SSc the clinical features are heterogeneous and disease course
variable, the introduction of new biomarkers is crucial to early
determine systemic complications.
Biomarkers are useful to predict disease activity and progression, to
identify patients at high risk of flares and monitor response to
treatment. In a large cohort of individual without plasma cell disorder,
the findings of FLC levels above the normal range proved to be
predictors of worse overall survival in the general population of
individual without plasma cell disorders [26]. The urinary levels of
polyclonal FLC strongly depend on the rate of production and serum
concentrations, on the range of proteinuria, presence of tubular damage
and the affinity of the tubules for all different FLC [27]. The
system of reabsorption by the proximal tubular is very efficient but
saturable. Measurement of uFLCs is most used in course of plasma cell
malignancy as multiple myeloma, with an excess of monoclonal k or λ FLC
[28].
On the other hand, the clinical significance of polyclonal FLC is to
monitor activity of the disease, especially in those characterized by
activation of the B such as ADs and chronic inflammatory disorders
[5].
In SSc, subclinical renal involvement is characterized by abnormal
resistive index [29], isolated reduction in glomerular filtration
rate (GFR) rate and reduced kidney reserve [30]. Livi et al
evaluated the renal functional reserve from response of the kidney to an
amino acid challenge in normotensive patients with normal renal function
and no urinary abnormalities [31]. They found in SSc patients an
abnormal activation of renal functional reserve (RFR). RFR is a
parameter to measure the ability of the undamaged kidney to increase GFR
in response to protein overload and it depends on the activation of
preglomerular vasodilating mechanisms. In SSc, a functional derangement
of vascular tone control is evident, favouring the prevalence of
vasoconstrictor over vasodilating factors.
The lack of correlation between serum and urinary FLC suggests the
kidney’s inability to reabsorb the sFLC produced. It is well known that
a high prevalence of silent renal changes is observed in SSc kidneys,
including a reduced renal blood flow [32].
In clinical practice, the polyclonal elevations of FLCs are observed in
patients with chronic kidney disease and high blood pressure [33].
However, in our study the mean value of eGFR in SSc patients was 93
ml/min and no differences were found between patients with and without
arterial hypertension with both serum and urinary FLC levels. Thus, we
can confirm that the clearance and loss of FLC is not GFR and
comorbidity dependent.
The continuous reabsorption and accumulation of sFLC within the proximal
tubule lumen led to inflammation, tubular cells apoptosis, activation of
redox pathways and production of profibrotic cytokines [34, 35]. In
the present study SSc patients with abnormal urine free k have higher
DAI, although there is a weak positivity. The analysis of both urine and
serum for the assessment of FLC levels offer a simplified route to
evaluating the presence of activity and severity disease in ADs. The
increased levels of uFLC in these patients could be the result of
non-specific polyclonal B cell activation as occurs in other ADs.
The FLC production observed in different systemic rheumatic autoimmune
diseases reflect the clone expansion of B cells with specific
autoreactivities [4]. Due to their short half-life, FLC may be
considered a direct biomarker of B cell activity, recently described
also in organo-specific autoimmune disorders [36]. Increased FLC
levels maybe a marker of disease severity and can be useful for
therapeutic monitoring or to assess recurrences investigating and
reporting the association between pathogenic viruses (SARS-Cov2) with
the development of inflammatory condition in autoimmune diseases.
In conclusion, we suggest that both serum and urinary levels of FLC
could be considered a reliable biomarker to early diagnosis and
monitoring of disease activity, leading to an optimization of specific
patients’ management.