PN is a common comorbidity in patients with PSS, and neurological involvement with pain and physical disability may be responsible for the reduced quality of life of patients [12]. The progression of PN associated with PSS is generally chronic and insidious, and its clinical presentation varies. Jaskólska et al. found that carpal tunnel syndrome (54%) and axonal sensorimotor neuropathy (22%) were most common in patients with PSS [13]. Polyneuritis occurs in approximately 1.8% of patients with PSS, and for most patients with PSS, peripheral neuropathy is frequently associated with risk factors for the development of systemic diseases or lymphoma [2]. In our study, 25% of PSS patients had peripheral neuropathy.
Among the 15 patients with PSS-PN, 8 cases (53.33%) had polyneuropathy, of whom 1 patient with motor-sensory polyneuropathy and 7 with sensory-predominant polyneuropathy. 4 patients showed mononeuritis and 3 manifested multiple mononeuritis. No patients with combined lymphoma were found.
There are less risk factors commented upon the literature. The pathophysiology of pSS-associated neuropathy remains unclear. Gemignani et al. suggested increasing age as a risk factor for the development of polyneuropathy in pSS patients [14]. Liampas et al. also observed increasing age as one of risk factors for developing PN [15]. A possible explanation is microangiopathic changes in the endoneurial vessels [14].
Font et al. reported that the appearance of ANA and anti-SSA antibodies was associated with the development of pure sensory neuropathy (PSN) in patients with pSS [16]. Tani et al. explained that anti-SSA and anti-SSB autoantibodies might cause dysfunction in the nodal and internodal regions of axons and small nerve fibres; anti-SSA and anti-SSB antibody-negative PSS mainly affected small nerve fibres; therefore, the pathophysiological basis of seronegative and seropositive PSS is different [17].
However, Sene et al. suggested that presence of B-cell activation markers was lower in non-ataxic sensory neuropathies (ANA, anti-SSA (Ro), anti-SSB (La), RF, hypergammaglobulinaemia) [18], and inversely demonstrated an association between sensorimotor pSS-related neuropathy and higher prevalence of B-cell monoclonal proliferation markers as well as chronic B-cell activation [18, 19], indicating that non-ataxic sensory neuropathies might belong to a subgroup of pSS with a peculiar peripheral sensory neurotropism.
Hsu et al. proposed anti-β2-glycoprotein-I (aβ2GP-I) and perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) levels as risks for the appearance of neuropathy in patients with pSS [20]. Jamilloux et al. suggested that cryoglobulinaemia was a unique risk of neurological manifestations, especially sensorimotor neuropathies and mononeuritis multiplex [21]. Similarly, Sene et al. found a strong association between sensorimotor neuropathies and presence of mixed cryoglobulins [19], suggesting that vasculitis is a possible pathogenetic mechanism for pSS-related peripheral neuropathy. Ye et al. also confirmed that sensorimotor polyneuropathies (SMP) was mainly sustained by vasculitis and immune-complex deposition disease, while pure sensory neuropathy might be caused by a direct immune-mediated damage [22]. However, no association between cryoglobulinaemia and vasculitis and peripheral neuropathy was found in this study, which may be related to the small sample size.
Cafaro et al. suggested that the negative prognostic factors, including purpura, extra-glandular manifestations, leukopenia, low complement and cryoglobulinaemia, mostly characterized patients with SMP, while those with pure sensory neuropathy demonstrated a milder type. These findings may suggest different pathogenic pathways on different types of PNS manifestations in PSS [23].
This study showed that patients with PSS combined with PN had a longer duration of disease and a higher incidence of Raynaud's phenomenon as well as positive anti-SSB antibodies, positive RF, and hyperglobulinaemia than the uncomplicated PN group. By logistic regression analysis, hyperglobulinaemia, RF, and anti-SSB antibodies were independent risk factors for the development of peripheral neuropathy in PSS (P < 0.05).
There are few reports on the treatment of PSS-PN, and there is a lack of RCTs with large samples. The recently published EULAR recommendations suggest first-line immunosuppressive therapy in patients with axonal sensory polyneuropathy [24]. Glucocorticoids are the most commonly used treatment option of managing pSS-related PN, when associated with vasculitis, followed by the use of IVIG [15].
Pindi Sala et al. presented their experience related to the persistent improvement of Ig in a case series of small-fibre neuropathy in Sjögren’s syndrome. The results show a major and persistent benefit of intravenous immunoglobulins (IvIG)/subcutaneous immunoglobulin (SCIg) longer treatments in patients with SFN-associated PSS, suggesting that adapted doses of Ig for periods of several months could have a major impact on long-term outcome [25]. Mekinian et al. observed 17 patients with PSS-PN treated with RTX and showed that 11 of them had remission of neurological symptoms, indicating that RTX may be effective for vasculitis-related PN in patients with PSS [26]. Hirsch et al. found that PSS and its complication polyneuropathy was associated with selenium deficiency [27]. Substitution of selenium may be a possible therapy of polyneuropathy associated with pSS.
Of the 15 patients with PN in our group, 14 patients were treated with glucocorticoids, 5 with mycophenolate mofetil, 8 with cyclophosphamide, 7 with hydroxychloroquine, 2 with methotrexate, 1 with azathioprine, 1 with rituximab, 1 with gamma globulin and 1 with belimumab. 10 patients had clinical remission (8 with partial remission and 2 with complete remission), indicating that immunosuppressive therapy was effective in patients with PSS-PN.
There are several limitations in this study. First, its sample size was small and did not satisfy the EPV (event per variable) requirement. Therefore, the results may not be robust enough. However, considering the rarity of this patient group and the interpretability of the results, they were still presented. Second, this was a single-centre study, and future multicentre collaborations are needed. Last, this was a retrospective analysis and easily induced bias of unmeasured factors.
In conclusion, PN is a common complication of PSS. Patients with PSS combined with PN have a longer duration of disease and a higher incidence of Raynaud's phenomenon, positive anti-SSB antibody, positive RF, and hyperglobulinaemia than those without PN. Hyperglobulinaemia, positive anti-SSB antibody and RF are independent risk factors for its occurrence. Immunosuppressive therapy is partially effective in alleviating PN.
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