Treatment of non-systemic Sjögren's syndrome: Potential prevention of systematization with immunosuppressant agent/biotherapy

Background Sjögren's syndrome (SS) is a systemic autoimmune pathology manifested mainly by a dry syndrome, intense asthenia and arthromyalgia. Systemic manifestations may also occur. Since 2019, immunosuppressant agents (IS) or biotherapies are recommended only for patients with systemic involvement. However, before 2019, in some cases, paucisymptomatic patients had been treated with IS/biotherapies, often off-label. Objective: We propose to evaluate the benefit and safety of using IS/biotherapy in patients with SS without systemic involvement. Methods: We retrospectively collected the clinical records of all patients with SS diagnosed according to ACR/EULAR diagnostic criteria followed up between January 1980 and October 2023 at Grenoble University Hospital (France). Results: Eighty-three patients were included: 64 with an initially non-systemic form. Of these patients with an initially non-systemic form, 24 were treated with IS/biotherapy. None of them developed secondary systematization, whereas 11 out of 40 patients in the untreated group did (p < 0.05). On the other hand, IS/biotherapy did not appear to improve dry syndrome. There were no serious adverse events. Conclusion: Early introduction of an IS/biotherapy treatment appears to provide a benefit for the patient without side effects.


Introduction
Sjögren's syndrome (SS) is a systemic autoimmune disorder with a tropism for exocrine glandular epithelia [1].Its main symptoms are dry eyes, dry mouth, gynecological dryness and dry skin [1].Associated with this dry syndrome, there is frequently intense asthenia and arthromyalgia [1].Systemic manifestations may also occur, mainly affecting lungs, lymph nodes and nerves [1].
This disease is far from rare: its prevalence is estimated between 0.6 and 1.5% of the general population.It mainly affects women (sex ratio F/M: 9/1), with a peak prevalence in the fifth decade [1].
Diagnosis is provided by the ACR/EULAR classification criteria of SS published in 2016 [1].It is primarily based on the presence of an objectified dry syndrome associated with the demonstration of autoimmunity directed against the glandular epithelium, with the presence of lymphocytes within the accessory salivary glands or the presence of serum autoantibodies directed against the SSA protein [1].
Treatment depends on the type of organ affected.When the symptomatic triad of dry syndrome, arthromyalgia-like pain and asthenia is present, purely symptomatic management is recommended, according to the EULAR recommendations [2] published in 2020 and the 'Protocole National de Diagnostic et de Soins' (PNDS) published in 2022 [3].It relies on topical or systemic treatments to reduce dry syndrome, notably with muscarinic agonists [2,3] such as pilocarpine [3][4][5][6], and pain, notably with the use of non-steroidal anti-inflammatory drugs (NSAID) or hydroxychloroquine (HCQ) [2,3].
Prior to the recommendations issued by the PNDS [3], IS or biotherapies were sometimes used in patients presenting the pathognomonic symptomatic triad with dry syndrome resistant to topical treatments, or presenting arthromyalgia with significant functional repercussions.Those treatments were often introduced to prevent secondary systematization of the disease, although no studies have demonstrated this hypothesis.
Moreover, the use of muscarinic agonists, which are recommended for dry syndrome resistant to topical treatment, is often limited by their tolerance.
We propose to evaluate the benefit and the safety of using IS agent or biotherapy in patients with Sjögren's syndrome without systemic involvement in Grenoble University Hospital.We will also evaluate the benefit of a muscarinic agonist, pilocarpine (the only agonist with marketing authorization in France), in dry syndrome in our population of patients followed in internal medicine for Sjögren's disease with or without systemic form.

Patients' selection
We retrospectively collected clinical files from all patients with SS diagnosed according to ACR/EULAR diagnosis criteria followed between January 1980 and October 2023 in the Grenoble University Hospital (France).
Exclusion criteria included follow-up of less than 6 months, absence of a dry syndrome or participation in a pilot study (due to lack of knowledge of the therapy delivered to the patient).The local medical ethics committee approved the study the 9/7/23 (named E2TMG3S) and oral informed consent was obtained from each patient.

Data analysis
Clinical data were extracted from medical records that we collected periodically in the internal medicine department at Grenoble University Hospital.We reviewed all clinical records of patients hospitalized or followed up in consultation in internal medicine to select all patients with ≥6 months of follow-up.
Systemic SS was defined according to the PNDS criteria [3] as a form not limited to the 'dry syndrome-arthromyalgia-asthenia' triad.Systemic manifestations could be hematological (cytopenia), pulmonary (diffuse interstitial lung disease), neurological (central or peripheral with abnormalities detected on imaging, lumbar puncture or electromyogram), articular -with the presence of arthritis-, renal, cutaneous -with the presence of vasculitis or purpura-, muscular -with the presence of myositis-.
ESSDAI ≥1 was not synonymous with systemic disease, given the presence of glandular, lymph node and joint manifestations such as arthralgia in the ESSDAI score.
Dry syndrome was subjectively assessed by the physician at the follow-up consultation.
A major improvement corresponds to a regression of the dry syndrome of more than 50%, a moderate regression to less than 50%.

Statistical analysis
All statistical tests were performed by using GraphPad PRISM 5.0 (GraphPad Software, Inc, La Jolla, Calif).
Continuous variables were presented as medians and ranges.Nonparametric Wilcoxon test was used for the comparison of two groups.One-way analysis of variance followed by Bonferroni correction was used to compare more than two groups.
Categorical variables were presented with counts and percentages and were compared using the Chi square test (if number of patient was >5 patients) or Fisher test.
Risk of systematization was compared between groups using survival analysis with log rank test.All tests were two-sided.All tests were considered significant when p < 0.05.

Results
Ninety-six patients were eligible to participate in this study.Thirteen were excluded: 10 because they did not meet the inclusion criteria (3 not meeting ACR/EULAR 2016 criteria [2], 5 did not complai of dry syndrome, 1 with less than 6 months follow-up, 1 included in a clinical trial) and 3 due to lack of information.Eighty-three subjects with SS were recruited for this study (Fig. 1).The clinical characteristics of the patients are presented in Table 1.Of all patients, 50 received one line of immunomodulatory treatment (IS/Biotherapy or HCQ), 37 two lines, 20 three lines, 7 four lines and 2 five lines of treatment (Table 2).Thirty nine patients received HCQ (30 with initially non-systematized SS form and 9 with initially systematized SS form).

Outcome of patients with non-systemic SS with or without IS/ Biotherapy
Sixty-four patients had a non-systemic disease at the start of followup in the internal medicine department.Of these, 24 were rapidly treated with IS agents or biotherapy (Table 2).Thirty patients received HCQ (15 in the IS/biotherapy group, 15 in the untreated group).Of the patient receiving HCQ, three showed improvement in dry syndrome and thirteen showed improvement in arthralgia.
Patients with a non-systemic form who received IS/biotherapy developed significantly less secondary systematization with increasing duration of follow-up (Fig. 2A).In fact, none of the IS/biotherapy treated patients developed secondary systematization during follow-up.
If we looked at the risk of systematization by separating patients with non-systemic SS according to the type of immunomodulatory treatment received (immunosupressant/biotherapy, HCQ or both combined), treatment with HCQ alone did not prevent systematization (Fig. 2B) (p < 0.001).
Finally, when we looked at the risk of systematization in patients with ESSDAI = 0, i.e. 59 patients (21 treated and 38 untreated with IS/ biotherapy), the risk of systematization was greater in untreated versus treated patients, but not significantly so (p = 0.059) (Fig. 2C).
Finally, we wondered whether patients with secondary systematization presented a particular profile compared to those without (Table 3).Age at the diagnosis (p < 0.05), the length of follow up (11 years vs. 19 years in patients without and with secondary systematization respectively (p < 0.01)), and systemic involvement were different between the two groups.

Outcome of patients with systemic form with or without IS/ Biotherapy
Of the 19 patients with systemic onset, 15 received IS/biotherapy.Four patients did not receive treatment despite a systemic form: 1 had a CNS form with white matter hypersignals, 1 had pulmonary involvement with bronchitis and bronchial dilatation, 1 had myositis which improved spontaneously, and 1 had a multivisceral form with hematological, neurological, articular and cutaneous involvement under investigation.HCQ treatment was given for a time to the patient with pulmonary involvement, but was ineffective.
When we looked at the risk of new systemic manifestations, there was no difference between the treated and untreated arms.Indeed, among the four untreated patients, only one presented a new systemic manifestation.This patient's initial multisystemic form worsened rapidly, with hematological and muscular involvement, before treatment with rituximab was initiated.Despite this treatment, she developed secondary cryoglobulinemia and died within 18 months of diagnosis.
In the treatment arm, one patient developed moderate proteinuria with an unlabeled glomerular profile after 11 years follow-up, despite well-managed treatment with rituximab.This proteinuria improved spontaneously.

Progression of dry syndrome with muscarinic agonist or with IS/ Biotherapy
We then studied the value of pilocarpine in improving dry syndrome in patients with SS.Sixteen patients received pilocarpine.Among them, two patients discontinued the treatment due to poor tolerance.When we look at the evolution of the dry syndrome, it did not differ between treated and untreated patients (Fig. 3A), with comparable dryness between the two groups and a comparable number of complications such as recurrent gingivo-stomatitis, recurrent parotiditis, tooth decay, blepharitis, conjunctivitis, keratitis, candidiasis (oral, genital).On the other hand, treated patients had fewer episodes of parotid swelling (Table 4).
We also looked at the efficacy of immunosuppressive therapies or biotherapy on dry syndrome.Those therapies did not change the course of the dry syndrome either (Fig. 3B).

IS/biotherapy tolerance
IS/biotherapy treatments were often well tolerated (Table 2).The most frequent adverse events were digestive disorders on methotrexate and abatacept, arthralgia and asthenia after a course of rituximab.Two treatments were discontinued because of infections: leflunomide because of skin abscesses, and tocilizumab because of repeated nonserious infections.Two cases of significant hepatic cytolysis (but without any drop in PT) were reported: one on azathioprine, one on methotrexate.

Discussion
SS is a chronic inflammatory disease with a polymorphic presentation for which no treatment has been shown to be effective [10][11][12][13].Indeed, to date, no clinical trial has shown significant improvement in the disease under treatment.However, this information must be qualified by the fact that few molecules have been tested in Phase 3 trials (only hydroxychloroquine [14], rituximab [12,13,15], abatacept [11] and etanercept [16]).Nevertheless, even in case analysis, few treatments appear to be effective.Some teams have reported some efficacy of rituximab on glandular involvement [12,15,[17][18][19][20].However, those results are debated, with other teams finding no evidence of efficacy [13,[21][22][23].This has led international specialists [2,3] to recommend purely symptomatic treatment for non-systemic disease, with immunosuppressive therapy or biotherapy reserved for the most severe forms, by extrapolation of data found for other autoimmune diseases, notably lupus [24].
It is therefore recommended that dry syndrome be treated first with topical agents, followed by muscarinic agonist if symptoms persist despite topical treatment [2].We also wanted to examine the efficacy of long-term pilocarpine on dry syndrome.In France, only pilocarpine is authorized as a muscarinic agonist, although it is considered less well tolerated than cevimeline [25].Pilocarpine has indeed demonstrated some efficacy in reducing oral and ocular dry syndrome [4,26,27], both subjectively and objectively at early stages (≤12 weeks), with an improvement in salivary flow and conjunctival inflammation (measured via conjunctival cellularity) [4].However, its efficacy has never been tested at more than 12 weeks' follow-up.The lack of difference between the pilocarpine-treated and non-treated groups of SS patients can be explained by the absence of objective measures in this study, but also by the lack of long-term efficacy of pilocarpine.Pipje et al. studied the evolution of the dry syndrome over time in patients with SS [28].They found a slight worsening of stimulated salivary flow and stimulated parotid glandular volume after 4 years of disease progression, but these were not associated with a worsening of the sensation of dry mouth or dry eyes [28].Nor is there any change in unstimulated salivary flow or glandular volume.In our study, we found no reduction in the risk of dry syndrome complications such as recurrent gingivo-stomatitis, recurrent parotiditis, tooth decay, blepharitis, conjunctivitis, keratitis, candidiasis (oral, genital).This raises the question of the value of this molecule as a long-term treatment, all the more so as it is often poorly tolerated [25], reducing patient compliance.Further studies to investigate the long-term efficacy of pilocarpine in preventing complications of dry syndrome would also appear to be necessary.Apart from symptomatic management of dry syndrome, it is recommended that patients with non-systemic SS have joint pain managed with NSAIDs, followed by HCQ if NSAIDs prove effective [2,3].In our study, this treatment improved joint pain in 31.5% of cases.However, it did not prevent systematization.In our study, where patients were followed-up for an average of 11 years, we can see that patients with a non-systemic form at the outset had a secondary risk of systematization, which increased with time.
The risk of systematization of the disease is well known [29], which has led various health authorities to recommend regular follow-up of patients with SS [2,3], and the introduction of treatment if systematization occurs.In our study, we can see that the introduction of IS or biotherapy in systemic forms is only effective in around 50% of cases.When introduced before systematization, it seems to prevent the   appearance of new manifestations.This is in line with findings for other chronic dysimmune diseases such as Behcet's disease or interferonopathies, where failure to control inflammation is associated with an increased risk of disease worsening [30,31].The value of treating all chronic inflammation is also increasingly debated, as the latter seems to favor both cardiovascular pathologies hitherto considered as atheromatous disease, and neuropsychiatric pathologies [32][33][34].The question remains as to which molecule to use and how to control inflammation.In our study, apart from leflunomide or tocilizumab, any IS or biotherapy seemed to prevent systematization.This should be weighed against the fact that prescribing physicians regularly changed treatment (>5% of patients received more than 4 lines) when they judged the current treatment to be ineffective.Dryness intensity does not seem to be a marker of systematization.In our study, it did not regress under immunosuppressive treatment.Those results are in line with other studies showing non-regression of dry syndrome under treatment [5, [21][22][23][24][25][26][27][28][29][30][31], both subjective and objective.As well, initial arthralgia do not appear to be a predictor of secondary systematization.In rheumatoid arthritis, the DAS28 not only assesses the number of swollen, painful joints, but also the subjective evaluation of the disease [35].A composite score taking into account objective disease assessment (such as IgM-RF, complement), salivary flow and subjective assessment using a visual analog scale, as is the case for DAS28, could be an interesting tool.
This study has several limitations.The duration of follow-up between the different forms varies: it is longer in patients with a secondarily systematized form than in patients with a non-systematized form.This may raise the question of a potential bias when comparing the risk of systematization in patients with an initially non-systematic form between the IS/biotherapy-treated group and the untreated group.Nevertheless, the Log Rank test normally takes these differences in follow-up time into account, and we can see that as early as 10 years, there is a difference between treated and non-treated groups.Another limitation is that the data were studied retrospectively.In addition, evaluation of dry syndrome was based solely on subjective assessment by the physician.Another limitation inherent to registry studies is that the clinical findings depend on physician expertise.
In conclusion, SS is a chronic disease with the risk of immediate or secondary systematization.Immunosuppressive treatments or biotherapy might prevent secondary systematization but further randomized studies are needed.

Funding statement
None.

Disclosure statement
None.

Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Fig. 1 .
Fig. 1.Flow diagram.Of a cohort of 96 patients, 83 patients were included with a confirmed Sjögren's syndrome.

Fig. 3 .
Fig. 3. Evolution of dry syndrome in patients with SS treated or not with pilocarpine (A) or IS/Biotherapy.A major improvement corresponds to a regression of the dry syndrome of more than 50%, a moderate regression to a regression of less than 50%.IS: immunosuppressant agent.

Table 1
Characteristics of SS patients.

Table 2
Immunotherapy on patients with or without initially systemic SS.
(continued on next page) A. Belbézier et al.

Table 3
Difference between patients with non-systemic SS form, secondary systemic SS form or initial systemic SS form.

Table 4
Characteristics of SS patients treated or not with pilocarpine.