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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

Sjögren's syndrome (SS)–related peripheral neuropathy is responsible for disability, but no treatment has been shown to improve its outcome. In some cases, intravenous immunoglobulin (IVIG) therapy has been associated with some benefit. In this study, we investigated the effectiveness of IVIG in SS-related peripheral neuropathy.

Methods

We assessed the efficacy and tolerance of IVIG in 19 patients with primary SS–related neuropathy without any necrotizing vasculitis in a retrospective national multicentric study. The evaluation of the response was assessed using the disability Modified Rankin Scale (MRS) and a global evaluation by the practitioner.

Results

Eight patients (42%) exhibited a decrease of the MRS score corresponding to a clinical improvement, 10 patients (52%) exhibited a stable MRS score, and 1 patient (6%) showed an increase of MRS score. According to the global evaluation by the practitioner, 9 (47%) of the 19 patients were improved, 6 patients (31%) were stable, and 4 patients (21%) worsened. All the patients with sensorimotor (n = 5) or nonataxic sensory neuropathy (n = 4) were improved or stabilized. However, among the patients with ataxic neuropathy (n = 9), only 2 improved and 4 worsened. Ten of the 13 patients treated with corticosteroids could have had the prednisone dosage decreased from 15 mg/day (range 7.5–60) to 10 mg/day (range 5–20) with IVIG. Only 1 patient stopped the treatment after 1 dose because of a minor side effect and lack of initial efficacy.

Conclusion

IVIG may be useful in the treatment of SS-associated sensorimotor neuropathies or nonataxic sensory neuropathy without any necrotizing vasculitis. The benefit of such therapy in the SS-related ataxic neuropathy seems less clear.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Primary Sjögren's syndrome (SS) is one of the most frequent autoimmune systemic diseases, characterized by lymphoid infiltration of exocrine glands responsible for sicca symptoms. Extraglandular involvement, such as peripheral neuropathy, might also occur. The spectrum of primary SS–related peripheral neuropathy is wide, including sensorimotor or painful sensory polyneuropathy, sensory ataxic neuropathy (sometimes called ganglionopathy), trigeminal neuropathy, autonomic neuropathy, multiple mononeuropathy, polyradiculoneuropathy, and multiple cranial neuropathy (1–4). The pathogenic mechanism responsible for most forms of SS-associated neuropathy remains unknown. When motor symptoms are present, necrotizing vasculitis diagnosed by neuromuscular biopsy results must be considered and, when present, usually may respond to immunosuppressive therapy (5). However, although it represents the majority of peripheral involvement in SS, peripheral neuropathy associated with another pathogenic mechanism (such as lymphocytic infiltration, loss of neuronal cell bodies, and clinical correspondence to sensory distal neuropathy or ganglionopathy) lacks efficient treatment (1–4, 6). In these cases, the best therapeutic option is not known (6), and corticosteroids, plasmapheresis, and conventional immunosuppressive drugs have been unsuccessful in comparison with their recognized benefit on the other systemic complications of SS (6).

Intravenous immunoglobulins (IVIGs) are therapeutic preparations of polyclonal human immunoglobulins, obtained from a pool of plasma from more than 1,000 healthy donors. IVIG is an established therapy for patients with chronic inflammatory demyelinating polyneuropathy, multifocal moto neuropathy, or Guillain-Barré syndrome (7, 8). The most common adverse events of IVIG are renal failure, congestive heart failure, and sometimes allergic reaction. Ten case reports have shown that IVIG may be an interesting therapeutic option in SS-related peripheral neuropathy, but the literature has given little evidence to clearly justify the use of this costly therapy for this disease (9–11). To further investigate the role of IVIG in SS-related peripheral neuropathy, we assessed the effect and the tolerance of this treatment in SS patients with neuropathy in a French retrospective multicentric study.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Patient selection.

All of the 1,400 French rheumatology and internal medicine practitioners registered on the Club Rhumatismes et Inflammation (CRI) network, which is part of the French Society of Rheumatology and a partnership with the French Society of Internal Medicine, were contacted by e-mail. Four successive monthly electronic newsletters were sent to collect observations of patients with primary SS who fulfilled American–European Consensus Group criteria (12) and who have received at least 1 infusion of IVIG for SS-related peripheral neuropathy. All data were reviewed by 2 authors (SR and JS) and collected using a standardized form that was also available on the CRI web site (www.cri-net.com). In the case of additional queries, the medical file was sent to the same authors or the practitioner was contacted directly.

Clinical assessment.

We noted all features for neurologic involvement, the type of neuropathy, the results of neuromuscular biopsy if performed, the modalities of IVIG administration, the concomitant treatments, and the followup. Efficacy and tolerance were also recorded. Evaluation of the response was assessed retrospectively by 2 separate and blinded investigators (JS and SR) and confirmed by the clinician directly involved in the followup of the patient, using the disability Modified Rankin Scale (MRS; where 0 = asymptomatic, 1 = nondisabling symptoms not interfering with lifestyle, 2 = mildly disabling symptoms leading to some restrictions of lifestyle but not interfering with capacity to look after oneself, 3 = moderately disabling symptoms significantly interfering with lifestyle or precluding totally independent existence, 4 = moderately severe disability precluding independent existence while not requiring constant attention around the clock, and 5 = severe disability with total dependency requiring constant attention day and night) (3). Clinical efficacy was also determined with a global evaluation based on the hospitalization report, taking into account the indications found in the medical file about pain evolution or degree of disability (e.g., “The patient does not burn her hands.” “The patient walked 10 minutes before treatment and now can walk 1 hour.”) and the general opinion of the practitioner based on the correspondences during the followup under treatment. The modification of concomitant symptomatic treatment prescribed for neuropathic pain (corticosteroids, analgesics) was also taken into account.

Statistical analysis.

Data were presented as median (range) or mean ± SD values. No statistical analysis has been performed since our population is heterogeneous in the clinical presentation and the administrated treatments.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Clinical features of patients.

Nineteen observations of SS fulfilling the American–European Consensus Group criteria and having a peripheral neuropathy treated by IVIG were collected from 5 centers (4 rheumatology centers and 1 internal medicine department; all specialized in systemic autoimmune diseases), including 2 national reference centers for systemic autoimmune diseases (Lille, Strasbourg). Table 1 shows the characteristics of the 19 patients according to the type of neuropathy. The mean age was 60 years (range 35–87 years), and there were 11 women and 8 (42%) men. Among the 19 patients, 9 (47%) had anti-SSA antibodies, 5 (26%) also had anti-SSB antibodies, and 16 patients (84%) had a pathologic salivary gland biopsy result with a focus score ≥1, including 10 patients (53%) with the biopsy finding as the solely objective immunologic criterion for SS diagnosis. The median duration of SS was 4 years (range 1–28 years) and the median duration since the diagnosis of the neuropathy was 9 years (range 2–22 years). All the patients had a peripheral neuropathy confirmed by electromyography that allowed, in combination with clinical examination, to classify neuropathies as follows: sensorimotor (n = 5), sensory (n = 4), ataxic (n = 9), and conduction block form related with monoclonal cryoglobulin IgM paraprotein (n = 1). In 6 cases, a neuromuscular biopsy had been performed showing non-necrotizing leucocytoclasic vasculitis in 2 cases; in the other cases, a nonvasculitic lymphocytic infiltrate (n = 3) was present and the biopsy result was without abnormality in 1 patient. The pretherapeutic median MRS score was 2.6 (range 1–4). Seven patients received immunosuppressive treatment alone or in combination for the neuropathic manifestations before IVIG: cyclophosphamide (n = 4), azathioprine (n = 5), mycophenolate mofetil (n = 3), hydroxychloroquine (n = 3), and rituximab (n = 2). Thirteen patients received oral prednisone (mean 10.5 mg daily). There was no other cause of neuropathy except for 1 patient who had chronic alcoholic intoxication.

Table 1. Characteristics of 19 patients with Sjögren's syndrome according to neuropathy type*
 Sensorimotor (n = 5)Ataxic (n = 9)Nonataxic sensory polyneuropathy (n = 4)Conduction block (n = 1)
  • *

    Values are the number unless indicated otherwise. IVIG = intravenous immunoglobulin; IS = immunosuppressive drug.

Women/men3/24/53/11/0
Age, mean (range) years49 (34–61)70 (41–86)52 (45–60)70
Positive anti-SSA and/or anti-SSB antibodies4221
Focus score ≥13940
Corticosteroid treatment before IVIG4621
IS treatment before IVIG2410
Duration of treatment, mean (range) months11.6 (4–21)13.4 (2–24)15.2 (4–32)14
IVIG courses, mean (range)12.8 (4–24)7.6 (1–24)14.25 (4–30)13
Followup, mean (range) months19.2 (16–21)32.2 (10–84)19 (3–31)66

Characteristics of the therapeutic regimen.

The median treatment duration was 7 months (range 2–32 months) and the median followup was 27 months (range 10–84 months). The details according to the type of neuropathy concerning treatment duration and followup are reported in Table 1. All the patients were treated initially with monthly IVIG (2 gm/kg of body weight on 5 days in 10 patients or on 2 days in 9 patients). Among those patients treated with IVIG, 12 patients received Tégéline (LFB), 6 received Sandoglobuline (CSL Berhing), and 1 received Octagam (Octapharma). Two patients received methylprednisolone (250 mg) at each IVIG infusion.

Efficacy of IVIG according to MRS score and global evaluation by the practitioner.

The change in the MRS score according to the type of neuropathy after IVIG treatment is shown in Figure 1. Eight patients (42%) exhibited a decrease in the MRS score, 10 patients (52%) had a stable MRS score, and 1 (6%) had an increase corresponding to a clinical aggravation. Neither the sensorimotor nor the nonsensory polyneuropathy form had an increase in the MRS score. Patients with ataxic neuropathy exhibited a stable MRS score under IVIG treatment, while the median MRS score of other neuropathy types decreased (Table 2).

thumbnail image

Figure 1. Variation of the Modified Rankin Score from baseline to after intravenous immunoglobulins according to the type of neuropathy. A, Ataxic neuropathy. B, Sensorimotor. C, Nonataxic sensory polyneuropathy. D, Conduction block.

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Table 2. Disease course under IVIG treatment according to the type of neuropathy evaluated using the judgment of the clinician*
 ImprovedStabilizedAggravatedMRS score, median (range)
Before IVIG treatmentDuring IVIG treatment
  • *

    Values are the number unless indicated otherwise. IVIG = intravenous immunoglobulin; MRS = Modified Rankin Scale; N/A = not applicable.

  • Azathioprine.

  • Mycophenolate mofetil.

Sensorimotor (n = 5)4103 (1–4)2 (1–4)
Ataxic neuropathy (n = 9)2343 (1–4)3 (1–3)
Nonataxic sensory polyneuropathy (n = 4)2201.5 (1–3)0 (0–2)
Conduction block (n = 1)10041
Associated methylprednisolone pulse110N/AN/A
Associated immunosuppressive drugs11 N/AN/A
IVIG courses, median (range)14 (6–35)3.5 (1–30)4.5 (2–12)N/AN/A
MRS score   N/AN/A
 Before IVIG2.52.72.5  
 After IVIG1.22.32.5  
Subjects with variation MRS score ≥1630N/AN/A
Followup, median (range) months24 (18–84)26.5 (10–36)28.4 (13–36)N/AN/A

Table 2 shows the efficacy of IVIG treatment according to the judgment of the clinician and depending on the type of neuropathy and the associated immunosuppressive treatment. All patients with sensorimotor (n = 5), nonataxic sensory neuropathy (n = 4), or conduction block (n = 1) were improved or stabilized. However, among the patients with ataxic neuropathy (n = 9), only 2 patients improved while 4 worsened. In these 4 patients who did not respond to IVIG treatment, the treatment was stopped after a median of 4 months (range 3–13 months) corresponding to a median of 4.5 infusions (range 2–12). In the 9 patients exhibiting a dramatic improvement during IVIG treatment, the efficacy was observed after 2 infusions. One of the patients with a ganglionopathy had an initial improvement, but a secondary treatment failure occurred after the ninth course of treatment.

Five patients (2 with sensorimotor neuropathy, 1 with nonataxic sensory polyneuropathy, 1 with conduction block, and 1 with ganglionopathy) could each have had their IVIG infusions spaced 2 or 3 months apart, after 1 year for 4 patients and after 4 months for 1 of the patients with sensorimotor involvement. Ten of the 13 patients treated with corticosteroids could have had the prednisone dosage decreased from 15 mg/day (range 7.5–60) before IVIG treatment to 10 mg/day (range 5–20) after IVIG treatment.

Tolerance.

Only 1patient stopped the treatment after 1 infusion because of a minor side effect (nausea) and lack of initial efficacy. No severe side effects were observed during the entire followup, especially thrombosis, renal failure, and neurologic manifestation.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Peripheral involvement of primary SS is difficult to manage since no treatment has clearly shown an ability to counteract the evolution of this complication, except in the case of the presence of a necrotizing vasculitis on neuromuscular biopsy samples (5). In the other cases, a therapeutic option allowing a stabilization or decrease of neurologic symptoms would be helpful and might avoid prescribing serial use of immunosuppressive agents associated with potential severe side effects and hypothetical efficacy. IVIG has been reported as a possible therapeutic alternative according to 10 cases reported in the literature (9–11). However, it is difficult to conclude if the use of this therapy is appropriate in SS-associated peripheral neuropathy, and how to administer it. Moreover, the choice of this therapy must take into consideration the economic impact of prescription costs, e.g., in France, 1 gram of Tégéline costs €42.5. Therefore, strong arguments regarding efficacy are needed to justify the choice of IVIG therapy in SS-related neuropathy. In this retrospective open-label study, we report that IVIG might be an interesting treatment for the chronic and disabling forms of primary SS–related peripheral neuropathy without necrotizing vasculitis. This study is the largest to evaluate the efficacy of IVIG in this type of complication. In previously reported cases, Mori et al report a benefit of IVIG, especially in painful sensory neuropathy and radiculoneuropathy, which is in accordance with our finding (3). However, those authors did not focus on the efficacy of this treatment, and no long duration of followup was available, which limits the evaluation of the long-term benefit of this therapy in this indication (3). In our study, we had a long duration of followup that was useful in accurately estimating the long-term benefit of IVIG.

Because of the gravity of peripheral neuropathy and the absence of efficient treatment, even the stabilization of clinical symptoms would be a valuable goal, since the natural course of this disease leads to a spontaneous and continuous aggravation. In our study, taking into account the evaluation by the clinician, 9 patients (47%) were improved, 6 patients (31.5%) had stable symptoms, and 4 patients had a clinical aggravation. The evaluation using the MRS score gave similar results: 8 patients (42%) exhibited a decrease in the MRS score, 10 patients (52%) exhibited no change, and the MRS score increased in 1 case (6%). The benefit of IVIG seems to depend on the type of neuropathy, i.e., all patients with sensorimotor (n = 5) or nonataxic sensory neuropathy (n = 4) were improved or stabilized according to the clinician evaluation. However, among the patients with ataxic neuropathy (n = 9), only 2 improved, and 4 were considered nonresponsive and the IVIG therapy was quickly stopped (usually after 2 infusions); 1 patient improved the first year, but then secondarily exhibited an aggravation that lead to stopping the IVIG after the twelfth course. Conversely, in the responders, the clinical benefit was observed after 2 courses of IVIG. Therefore, these results suggest that at least 2 courses of IVIG should be administered before making conclusions about the effect of IVIG therapy on SS-related peripheral neuropathy.

Some authors have suggested that the clinical benefit of IVIG therapy may appear rapidly after the first or second infusion in ataxic sensory neuropathy (10, 13). Consequently, further studies are necessary to investigate the optimal number of IVIG courses necessary to definitively assess the efficacy or the failure of the treatment, as well as to know how long to continue the treatment. These studies should probably focus on one type of neuropathy, most likely the sensorimotor or nonataxic sensory polyneuropathy.

Inherent biases should be noted in our study, such as selection bias, which we tried to limit by contacting a large number of clinicians dedicated to autoimmune diseases, especially SS. Obviously, we have missed some cases, most notably those cases that did not respond to IVIG therapy. Moreover, IVIG therapies may have a placebo effect related with the intravenous administration of the treatment. The evaluation of clinical response to therapy was retrospective and used subjective clinical tools (MRS score and opinion of the practitioner) per usual in the case of sensitive symptoms. However, we have used the MRS score, which is a validated scale, and we assessed each case by 2 independent investigators (SR and JS) with the help of the involved clinicians who were directly managing the cases.

Taking our results into account, from a practical point of view, symptomatic treatment should be tested in patients with SS without necrotizing vasculitis–related neuropathy. In this case, IVIG treatment may be tried for at least 2 courses (and, therefore, an evaluation made at the time of the third course). Although IVIG therapy has been suggested in the ataxic neuropathy corresponding to a very severe subtype of neuropathy, this presentation seems to respond less efficiently than the others to IVIG treatment. Moreover, if efficient, the treatment duration remains unknown.

Finally, we have noticed that despite the selection bias of this retrospective study, there is an excess of men (n = 8, 42%) compared with the usual distribution of SS patients (14). Moreover, the positivity of anti-SSA and anti-SSB antibodies was found less often than expected in a population of SS cases with approximately half of the patients fulfilling SS diagnosis criteria because of a focus score ≥1. These results suggest that SS neuropathy may occur preferentially in a particular subtype of patient, possibly with new autoantibody specificity; this remains to be further delineated.

In conclusion, SS may be complicated by a wide range of neuropathic manifestations responsible for disability and without an efficient proven treatment. IVIG may be useful in the treatment of refractory SS–associated sensory and sensorimotor neuropathies without any necrotizing vasculitis. The benefit of such therapy in the SS ataxic neuropathy seems less clear. Randomized controlled studies are needed to confirm the efficacy of IVIG in this indication.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Drs. Mariette and Sellam had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Rist, Sellam, Hachulla, Sordet, Puéchal, Hatron, Benhamou, Sibilia, Mariette.

Acquisition of data. Rist, Sellam, Hachulla, Sordet, Puéchal, Hatron, Benhamou, Sibilia, Mariette.

Analysis and interpretation of data. Rist, Sellam, Hachulla, Sordet, Puéchal, Hatron, Benhamou, Sibilia, Mariette.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  • 1
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