SEARCH

SEARCH BY CITATION

Keywords:

  • Primary Sjögren's syndrome;
  • Peripheral neuropathy;
  • Neuromuscular biopsy;
  • Vasculitis

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Objective

To evaluate the clinicobiologic presentation in patients with primary Sjögren's syndrome (SS)–related peripheral neuropathy, the histologic results of neuromuscular biopsy (NMB), and clinical outcome, and to identify prognostic factors.

Methods

We retrospectively studied clinical and biologic presentation of 40 patients with primary SS–related neuropathy who underwent NMB. Prognostic factors of clinical outcome were assessed by univariate and multivariate analysis.

Results

Patients with vasculitis (lymphocytic [n = 8] or necrotizing [n = 14]) had a higher prevalence of acute-onset neuropathy, multiple mononeuropathy, sensorimotor involvement, vascular purpura, general symptoms, increased C-reactive protein level, positivity for rheumatoid factor, hypocomplementemia, and monoclonal gammopathy compared with those without vasculitis (n = 18). Comparison between patients with necrotizing or lymphocytic vasculitis did not reveal significant differences in clinical or biologic presentation except for the presence of general symptoms and rheumatoid factor. Regarding clinical evolution, the results of NMB (P < 0.0001), in particular the presence of necrotizing vasculitis (P < 0.001), an acute neuropathy onset (P < 0.0001), general symptoms (P < 0.0001), multiple mononeuropathy (P = 0.0007), presence of sensorimotor involvement (P = 0.002), and increased C-reactive protein level (P = 0.008), were significantly associated with a better outcome in univariate analysis. In multivariate analysis, NMB resulting in the identification of patients with necrotizing vasculitis was the only variable that remained significantly associated with a better outcome (P = 0.01).

Conclusion

NMB is necessary to identify patients with necrotizing vasculitis, who have a better response to immunosuppressive therapy. NMB might therefore have both a diagnostic and prognostic relevance in primary SS–related neuropathy.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Sjögren's syndrome (SS) is one of the most frequent autoimmune systemic diseases, characterized by lymphoid infiltration of exocrine glands responsible for sicca symptoms. SS may be secondary to other autoimmune diseases or primary. Extraglandular involvement may occur and includes nervous system, musculoskeletal, pulmonary, renal, hematologic, intestinal, vascular, and/or dermatologic involvement (1). The spectrum of primary SS–related peripheral neuropathic features is wide, including sensorimotor or painful sensory polyneuropathy, ganglionopathy (sensory ataxic neuropathy), trigeminal neuropathy, autonomic neuropathy, multiple mononeuropathy, polyradiculoneuropathy, and multiple cranial neuropathy (2–11). The pathogenic mechanisms of neurologic involvement in primary SS are still unclear: vasculitic process (2, 4, 8, 10, 11), lymphocytic infiltration of the dorsal ganglia (7, 12), or antineuronal autoantibodies (13–15). The clinical course of primary SS–related peripheral neuropathy is variable, and data on clinical, biologic, and histologic characteristics at diagnosis, in particular the relevance of neuromuscular biopsy (NMB), and their relationship with evolution are very limited in the literature.

We hypothesized that the presence of vasculitis on NMB might be associated with different clinical features and outcome. We therefore evaluated the clinical and biologic presentation and outcome of 40 patients with primary SS and neuropathy in whom NMB was performed.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Patient selection.

All French rheumatology and internal medicine practitioners registered on the Club Rhumatismes et Inflammation Web site (1,400 physicians) were contacted by 3 successive electronic newsletters to collect observations of patients with primary SS, according to the American-European Consensus Group (AECG) criteria (16), who had a peripheral neuropathy and who underwent NMB. Moreover, 3 reference laboratories of neuropathology were contacted. All patient files were reviewed by BT and J-EG and were collected using a standardized form.

Clinical assessment.

All features of neurologic involvement and other extraglandular manifestations were noted. Electromyography with motor and sensory nerve conduction analysis was assessed. Tolerance and efficacy of treatments were also recorded. Evaluation of the response to therapy was retrospectively assessed by BT and J-EG using the disability Modified Rankin Scale (MRS; 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, 5 = severe disability with total dependency requiring constant attention day and night) (11). Response to therapy was evaluated by the difference in MRS score before treatment and 6 months after treatment initiation. Response was divided into good response (decrease in MRS score of ≥2 points), moderate response (decrease in MRS score of 1 point), stabilization, and worsening (increase in MRS score of ≥1 point).

Neuromuscular biopsy.

Sural nerve and muscle biopsy specimens were conventionally processed for light microscopy, as previously reported (17). In all cases but 5, the biopsy specimens were reviewed by the same neuropathologist (CL), who works in a reference center for peripheral neuropathy. The pathologist assessed the histologic slides blinded to the clinical features and evolution of the patients. The presence of inflammatory vascular lesions was evaluated in both muscle and nerve samples and was classified according to the diameter of the largest affected vessel (small or medium vessels), the type of inflammatory cells, and the presence of fibrinoid necrosis, as previously described (18).

Laboratory tests and radiographic measurements.

The results of standard laboratory tests, of all available immunologic data, and of human immunodeficiency virus, hepatitis B virus, and hepatitis C virus serologies were collected. Erythrocyte sedimentation rate was not included in the analysis because it was only rarely measured. Radiographs of the hands and feet of all patients were systematically reviewed.

Statistical analysis.

Data were presented as the median for continuous variables and the percentage for qualitative variables. Fisher's exact test was used to compare qualitative variables, and the nonparametric Mann-Whitney test to compare continuous variables. The choice to use Mann-Whitney tests was supported by our prior clinical hypothesis, leading to the main comparison between 2 groups (with/without vasculitis). P value ≤0.05 was considered significant.

Mann-Whitney tests were used to compare clinical change (e.g., difference in MRS score before and after treatment) according to baseline clinical, biologic, and histologic variables. The independent role of these variables was assessed using multiple linear regression. We introduced into the model the variables that remained associated with clinical change (P ≤ 0.20) after adjustment for histologic results in bivariate analysis. Statistical analyses were performed using Stata SE 9.2 (StataCorp, College Station, TX).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Clinical features of patients.

Fifty-one observations were collected from 19 centers, including 9 cases collected from the 3 neuropathology laboratories. Eleven were excluded because of incomplete diagnostic criteria for primary SS according to the AECG (16) (n = 2), diagnosis of rheumatoid arthritis associated with SS (n = 1), less than 6 months of followup (n = 6), and hepatitis C virus infection (n = 2). Hepatitis C serology was negative in all the remaining patients. Thus, 40 observations could be analyzed.

Neuropathy was diagnosed prior to primary SS in 25 patients (63%), with a median interval of 12 months (range 1–253). In 2 patients (5%), both conditions were diagnosed simultaneously, and in 13 (32%), neuropathy was diagnosed after primary SS, with a median interval of 24 months (range 5–228). The main clinical forms of neuropathy and neurologic symptoms are summarized in Table 1.

Table 1. Initial clinical features of 40 patients with primary SS with peripheral neuropathy in whom neuromuscular biopsy was performed*
FeatureValue
  • *

    Values are the number/total number (percentage) unless otherwise indicated. SS = Sjögren's syndrome; MRI = magnetic resonance imaging; pANCA = perinuclear antineutrophil cytoplasmic antibody.

  • ≤5 mm in 5 minutes.

  • ≤1.5 mm in 15 minutes.

  • §

    Focal lymphocytic sialoadenitis with a focus score ≥1.

  • Neuropathy onset <1 month before biopsy.

  • #

    Fever, severe asthenia, or weight loss >10%.

  • **

    At the time of diagnosis. The fourth case of lymphoma occurred after 10 years of followup.

Epidemiologic features 
 Sex, no. female:male33:7
 Age at diagnosis of primary SS, median (range) years56.5 (24–78)
 Age at diagnosis of neuropathy, median (range) years55 (29–79)
 Followup, median (range) months79 (13–300)
Diagnostic criteria for primary SS 
 Dry eyes36/40 (90)
 Dry mouth40/40 (100)
 Pathologic Schirmer's test24/27 (89)
 Decreased salivary flow10/13 (77)
 Pathologic salivary gland biopsy§37/39 (95)
 Anti-SSA antibody26/40 (65)
 Anti-SSB antibody17/40 (43)
Characteristics of neuropathy 
 Onset 
  Acute-onset neuropathy6/40 (15)
 Type 
  Multiple mononeuropathy11/40 (28)
  Polyneuropathy25/40 (62)
  Ganglionopathy5/40 (13)
  Trigeminal neuropathy1/40 (3)
 Clinical symptoms 
  Pure superficial sensory5/40 (13)
  Profound with or without superficial sensory13/40 (32)
  Sensorimotor22/40 (55)
 Electromyography 
  Sensorimotor involvement29/39 (74)
  Axonal impairment35/39 (90)
  Axonal and demyelinating impairment3/39 (8)
 Initial Modified Rankin Scale score, median (range)3 (1–5)
Extraglandular features of primary SS 
 General symptoms#12/40 (30)
 Vascular purpura11/40 (28)
 Central nervous system involvement7/40 (18)
  MRI white matter lesions2
  Spinal cord involvement2
  Cognitive impairment1
  Brain involvement mimicking multiple sclerosis1
  Optic neuritis1
  Motor neuron involvement1
 Lymphoma3/40 (8)**
Biologic features 
 Increased C-reactive protein level16/40 (40)
 Rheumatoid factor22/38 (58)
 Cryoglobulinemia15/40 (38)
 Hypocomplementemia13/34 (38)
 Monoclonal gammopathy9/40 (23)
 Increased β2-microglobulin level8/23 (35)
 pANCA4/38 (11)

The initial median MRS score was 3 in all patients (range 1–5). Three patients with vasculitis (2 lymphocytic and 1 necrotizing) had a maximal MRS score of 5.

At the time of diagnosis of peripheral neuropathy, 27 patients (68%) had other extraglandular involvement (Raynaud's phenomenon and arthralgias excepted), including synovitis (n = 5), vascular purpura (n = 11), muscular (n = 6), central nervous system (n = 7), pulmonary (n = 4), renal involvement (n = 2), and lymphoma (n = 3).

Histologic characteristics of patients.

Thirty-four patients underwent NMB, 3 underwent nerve biopsy, and 3 underwent muscle biopsy. Most of the histologic samples (85%) were reviewed by the same neuropathologist: the histologic slides of 5 patients were not available (3 patients with a histologic report excluding vasculitis, 1 with lymphocytic vasculitis, and 1 with necrotizing vasculitis). Eighteen patients showed no vasculitis but neurogenic atrophy, 8 patients had lymphocytic vasculitis, and 14 patients had necrotizing vasculitis (Figure 1). Among these patients with necrotizing vasculitis, medium vessel involvement was documented in 4 patients and small vessel involvement in 3. The diameter of the largest affected vessel could not be assessed in 7 patients, because no healthy segment of the affected vessel could be identified, given the intensity of the necrotizing process.

thumbnail image

Figure 1. A, Muscle biopsy sample: neurogenic atrophy. B, Nerve biopsy sample: lesions of lymphocytic vasculitis of small vessels, with infiltration by mononuclear cells. C, Muscle biopsy sample: lesions of necrotizing vasculitis with fibrinoid necrosis of small and medium muscular vessels. D, Nerve biopsy sample: epineural arterioles infiltrated by inflammatory mononuclear cells and neutrophils with fibrinoid necrosis and occlusion of the arterial lumen.

Download figure to PowerPoint

Association between the initial presentation and the results of NMB.

Clinical and biologic features differentiated patients with vasculitis from patients without vasculitis. Patients with vasculitis showed a higher prevalence of acute neuropathy onset (27% versus 0%; P = 0.02), multiple mononeuropathy (50% versus 0%; P = 0.0003), sensorimotor involvement (77% versus 28%; P = 0.004), general symptoms (45% versus 11%; P = 0.04), and vascular purpura (45% versus 6%; P = 0.01) than patients without vasculitis (Table 2). Patients with vasculitis also showed a significantly lower prevalence of profound sensory involvement (9% versus 61%; P = 0.0007) than those without vasculitis, and a clinical diagnosis of ganglionopathy, even associated with another form of neuropathy, was never associated with vasculitis on NMB.

Table 2. Initial clinical features of 40 patients with primary SS–related neuropathy according to the results of neuromuscular biopsy*
 No vasculitis (n = 18)LV (n = 8)NEV (n = 14)P (LV vs NEV)P (vasculitis vs no vasculitis)
  • *

    Values are the number/total number (percentage) unless otherwise indicated. LV = lymphocytic vasculitis; NEV = necrotizing vasculitis; NS = not significant; NR = not relevant; see Table 1 for additional definitions.

  • All P values >0.25 are reported as NS.

  • Neuropathy onset <1 month before biopsy.

  • §

    At the time of diagnosis. The fourth case of lymphoma occurred after 10 years of followup.

Epidemiologic features     
 Sex, no. female:male13:57:113:1NSNS
 Age at diagnosis of primary SS, median (range) years53 (36–77)60.5 (24–71)64 (35–78)NSNS
 Age at diagnosis of neuropathy, median (range) years51 (37–76)57.5 (29–67)62 (39–79)0.17NS
 Followup of neuropathy, median (range) months79 (13–233)116 (84–300)45.5 (30–228)0.003NS
Characteristics of neuropathy     
 Onset     
  Acute-onset neuropathy0/18 (0)0/8 (0)6/14 (43)0.050.02
 Type     
  Multiple mononeuropathy0/18 (0)2/8 (25)9/14 (64)0.180.0003
  Polyneuropathy14/18 (78)6/8 (75)5/14 (36)0.180.10
  Ganglionopathy5/18 (28)0/8 (0)0/14 (0)NR0.01
 Clinical symptoms     
  Pure superficial sensory2/18 (11)2/8 (25)1/14 (7)NSNS
  Profound with or without superficial sensory11/18 (61)1/8 (12)1/14 (7)NS0.0007
  Sensorimotor5/18 (28)5/8 (63)12/14 (86)NS0.004
 Electromyogram     
  Sensorimotor involvement10/18 (56)6/8 (75)13/13 (100)NS0.03
 Initial Modified Rankin Scale score, median (range)3 (2–4)3 (1–5)3 (2–5)NSNS
Extraglandular features of primary SS     
 General symptoms2/18 (11)1/8 (12)9/14 (64)0.030.04
 Vascular purpura1/18 (6)4/8 (50)6/14 (43)NS0.01
 Central nervous system involvement4/18 (22)2/8 (25)1/14 (7)NSNS
 Lymphoma§1/18 (11)1/8 (12)1/14 (7)NSNS
Biologic features     
 Anti-SSA antibodies9/18 (50)7/8 (88)10/14 (71)NS0.10
 Anti-SSB antibodies5/18 (28)5/8 (63)7/14 (50)NS0.12
 Increased C-reactive protein level1/18 (6)3/8 (38)12/14 (86)0.05<0.0001
 Rheumatoid factor6/17 (35)4/8 (50)12/13 (92)0.0480.02
 Cryoglobulinemia4/18 (22)4/8 (50)7/14 (50)NS0.10
 Hypocomplementemia3/16 (19)3/7 (43)7/11 (64)NS0.04
 Polyclonal hypergammaglobulinemia2/18 (11)3/8 (38)6/14 (43)NS0.07
 Monoclonal gammopathy1/18 (6)3/8 (38)5/14 (36)NS0.03
 Increased β2-microglobulin level2/11 (18)1/5 (20)5/7 (71)0.240.19
 pANCA0/18 (0)2/8 (25)2/12 (17)NS0.11

Patients with vasculitis showed a higher prevalence of increased C-reactive protein level (68% versus 6%; P < 0.0001), positivity for rheumatoid factor (76% versus 35%; P = 0.02), hypocomplementemia (56% versus 19%; P = 0.04), and monoclonal gammopathy (36% versus 6%; P = 0.03), and a tendency toward more frequent polyclonal hypergammaglobulinemia (41% versus 11%; P = 0.07), cryoglobulinemia (50% versus 22%; P = 0.10), anti-SSA/Ro antibodies (77% versus 50%; P = 0.10), anti-SSB/La antibodies (55% versus 28%; P = 0.12), antineutrophil cytoplasmic antibody (ANCA; perinuclear ANCA with [n = 1] or without [n = 3] myeloperoxidase specificity; 20% versus 0%; P = 0.11), and increased serum β2-microglobulin level (50% versus 18%; P = 0.19).

Comparison between patients with necrotizing vasculitis and those with lymphocytic vasculitis did not reveal any significant differences in clinical and biologic presentation, except for the more frequent presence of general symptoms (64% versus 12%; P = 0.03) and rheumatoid factor positivity (92% versus 50%; P = 0.048) in patients with necrotizing vasculitis. Likewise, patients with necrotizing vasculitis more frequently showed a tendency toward acute onset of neuropathy (43% versus 0%; P = 0.05), increased C-reactive protein level (86% versus 38%; P = 0.05), and increased serum β2-microglobulin level (71% versus 20%; P = 0.24) than patients with lymphocytic vasculitis. Cryoglobulin was found at the same frequency (50%) in both groups.

Characteristics of the initial therapeutic regimen.

Thirty-eight patients (95%) received initial treatment with corticosteroids including oral prednisone in 16 (40%) and pulse methylprednisolone in 22 (55%). Twenty-four patients (60%) received initial immunosuppressant agents, as summarized in Table 3. Among the 3 patients with lymphoma, chemotherapy with a CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) was used as initial therapy in 1 patient, rituximab and cyclophosphamide were used as initial therapy in 1 patient, and one patient received corticosteroids and azathioprine.

Table 3. Initial treatment and clinical outcome of peripheral neuropathy in 40 patients with primary Sjögren's syndrome*
 Value
  • *

    Values are the number/total number (percentage) unless otherwise indicated. CHOP = cyclophosphamide, doxorubicin, vincristin, prednisone; MRS = Modified Rankin Scale.

  • Good response is defined as a decrease in MRS score of ≥2 points.

  • Moderate response is defined as a decrease in MRS score of 1 point.

  • §

    Stabilization is defined as a stable MRS score.

  • Worsening is defined as an increase in MRS score of ≥1 point.

  • #

    Relapse is defined as an increase in MRS score of ≥1 point after previous improvement or stabilization.

Initial treatment 
 Corticosteroids38/40 (95)
  Oral prednisone16/40 (40)
  Pulse of methylprednisolone22/40 (55)
 Immunosuppressant agents24/40 (60)
  Azathioprine alone8/40 (20)
  Cyclophosphamide10/40 (25)
  Hydroxychloroquine3/40 (8)
  Rituximab plus cyclophosphamide1/40 (3)
  Methotrexate1/40 (3)
  CHOP regimen1/40 (3)
 Plasma exchange4/40 (10)
 Intravenous immunoglobulins0/40 (0)
Outcome 
 MRS score, median (range) 
  Before treatment3 (1–5)
  After treatment2 (0–5)
 Good response12/40 (30)
 Moderate response9/40 (23)
 Stabilization§17/40 (42)
 Worsening2/40 (5)
 Patients with clinical relapse#19/40 (48)
 Median number of relapses (range)2 (1–6)

Comparison between patients with and without vasculitis showed a similar use of corticosteroids (including oral prednisone and pulse methylprednisolone; 95% versus 94%) and immunosuppressant agents (64% versus 56%), except for a more frequent use of intravenous cyclophosphamide (36% versus 11%; P = 0.08) in patients with vasculitis (Table 4). Comparison between patients with necrotizing vasculitis and lymphocytic vasculitis did not reveal significant differences in therapy. However, patients with necrotizing vasculitis tended to more frequently receive intravenous cyclophosphamide (50% versus 13%; P = 0.17), with a significantly earlier initiation of treatment (11 weeks versus 80.5 weeks; P = 0.006).

Table 4. Initial treatment and clinical outcome of peripheral neuropathy in 40 patients with primary Sjögren's syndrome according to the results of neuromuscular biopsy*
 No vasculitis (n = 18)LV (n = 8)NEV (n = 14)P (LV vs NEV)P (vasculitis vs no vasculitis)
  • *

    Values are the number/total number (percentage) unless otherwise indicated. LV = lymphocytic vasculitis; NEV = necrotizing vasculitis; NS = not significant; MRS = Modified Rankin Scale; NR = not relevant.

  • All P values >0.25 are reported as NS.

  • Good response is defined as a decrease in MRS score of ≥2 points.

  • §

    Moderate response is defined as a decrease in MRS score of 1 point.

  • Stabilization is defined as a stable MRS score.

  • #

    Worsening is defined as an increase in MRS score of ≥1 point.

  • **

    Relapse is defined as an increase in MRS score of ≥1 point after previous improvement or stabilization.

Initial treatment     
 Delay neuropathy treatment, median (range) weeks52 (2–308)80.5 (8–1,256)11 (0–216)0.0060.12
 Corticosteroids17/18 (94)7/8 (88)14/14 (100)NSNS
  Pulse of methylprednisolone8/18 (44)4/8 (50)10/14 (71)NSNS
 Immunosuppressant agents10/18 (56)5/8 (62)9/14 (64)NSNS
  Cyclophosphamide2/18 (11)1/8 (13)7/14 (50)0.170.08
Outcome     
 MRS score, median (range)   0.030.0002
  Before treatment3 (2–4)3 (1–5)3 (2–5)  
  After treatment3 (2–4)2 (1–5)1 (0–3)  
 Good response0/18 (0)2/8 (25)10/14 (71)0.070.0001
 Moderate response§5/18 (28)2/8 (25)2/14 (14)NSNS
 Stabilization11/18 (61)4/8 (50)2/14 (14)0.140.05
 Worsening#2/18 (11)0/8 (0)0/14 (0)NRNS
 Patients with clinical relapse**11/18 (61)4/8 (50)4/14 (29)NS0.20
 Median number of relapses (range)2 (1–6)3.5 (2–5)1.5 (1–2)0.11NS
 Complications11/18 (61)5/8 (63)12/14 (86)NSNS
  Corticosteroids9/18 (50)4/8 (50)11/14 (79)NSNS
  Infections4/18 (22)4/8 (50)8/14 (57)NS0.05
 Dead or lost to followup2/18 (11)2/8 (25)4/14 (29)NSNS

Association between clinical change and therapeutic response profiles with the results of NMB.

Median initial MRS score was similar in all groups: 3 (range 2–4) in the group with no vasculitis, 3 (range 1–5) in the group with lymphocytic vasculitis, and 3 (range 2–5) in the group with necrotizing vasculitis (Table 4). The median followup duration was 71.5 months (range 8–277) for primary SS and 79 (range 13–300) for neuropathy. The median MRS score in all patients decreased from 3 to 2 (range 0–5) after 6 months of treatment.

Good response to therapy, assessed 6 months after initiation of treatment, was significantly more frequent in patients with than those without vasculitis (55% versus 0%; P = 0.0001). This better response rate was explained by a better response in patients with necrotizing vasculitis than those with lymphocytic vasculitis (71% versus 25%; P = 0.07). Moreover, a significant decrease between median MRS score before and after treatment was observed only in patients with necrotizing vasculitis (from 3 to 1; P = 0.0005), and not in patients without vasculitis (from 3 to 3; P = 0.38) or with lymphocytic vasculitis (from 3 to 2; P = 0.13).

Nineteen patients received a second-line treatment for clinical relapse or worsening, and 18 were treated with corticosteroids, including pulse methylprednisolone in 8 (44%). Fifteen (79%) received immunosuppressant agents, with a median number of 2 additional lines of treatment (range 1–5), including intravenous immunoglobulins (n = 6); azathioprine (n = 5); rituximab (n = 5); cyclophosphamide (n = 4); hydroxychloroquine (n = 3); methotrexate (n = 2); infliximab (n = 2); mycophenolate mofetil (n = 2); colchicine, plasmapheresis, interferon-α, and CHOP in 1 case each; and interferon-β and mitoxantrone hydrochloride in a patient with brain involvement mimicking multiple sclerosis.

Tolerance of treatments and mortality.

Sixteen patients (40%) developed at least 1 infectious complication, 4 without vasculitis and 12 with vasculitis (22% versus 55%; P = 0.05), including 4 with lymphocytic vasculitis (50%) and 8 with necrotizing vasculitis (57%). These infections included pyelonephritis (n = 7), sinusitis (n = 4), erysipelas (n = 4), pneumopathy (n = 4), candidosis (n = 2), and adenitis (n = 1). All of these patients had been previously treated with corticosteroids and 14 (88%) had received immunosuppressant agents. Other complications of corticosteroid use (including osteoporosis, bone fracture, osteonecrosis, infections, cataract, diabetes, psychiatric troubles, ponderal overload) occurred in 24 patients (60%), 9 without vasculitis (50%), 4 with lymphocytic vasculitis (50%), and 11 with necrotizing vasculitis (79%). Three patients (9%) died: one of an unknown cause, another of bacterial pneumopathy, and the last of refractory vasculitis.

Prognostic factors of evolution and response to therapy.

The univariate analysis of the factors predicting evolution (e.g., difference in MRS score before and after treatment) showed that the features that individually correlated with a better evolution were the results of NMB (P < 0.0001), in particular the presence of necrotizing vasculitis (P < 0.001) or lymphocytic vasculitis (P = 0.14), an acute neuropathy onset (P < 0.0001), general symptoms (P < 0.0001), multiple mononeuropathy (P = 0.0007), the presence of sensorimotor involvement (P = 0.002), and increased C-reactive protein level (P = 0.008). Monoclonal gammopathy (P = 0.06), rheumatoid factor (P = 0.16), and delay between diagnosis and initiation of treatment (P = 0.32) were not significantly associated with outcome. Multiple linear regression explored the independent role of these variables in the change in neuropathy under therapy. Results of this analysis indicated that NMB resulting in the identification of patients with necrotizing vasculitis was the only variable that remained significantly associated with a better outcome (P = 0.01) (Table 5).

Table 5. Univariate and multivariate analyses of the prognostic role of clinical, biologic, and histologic variables according to difference in Modified Rankin Scale score before and after treatment*
VariablesP
  • *

    NMB = neuromuscular biopsy.

  • Neuropathy onset <1 month.

  • Fever, severe asthenia, or weight loss >10%.

  • §

    Neuromuscular biopsy was significantly associated with clinical change in all bivariate analysis models.

Univariate analysis 
 Acute neuropathy onset<0.0001
 Clinical sensorimotor involvement0.002
 Multiple mononeuropathy0.0007
 General symptoms<0.0001
 Vascular purpura0.54
 Increased C-reactive protein level0.008
 Rheumatoid factor0.16
 Cryoglobulinemia0.35
 Hypocomplementemia0.23
 Polyclonal hypergammaglobulinemia0.23
 Monoclonal gammopathy0.06
 NMB<0.0001
  Lymphocytic vasculitis0.14
  Necrotizing vasculitis on NMB<0.001
 Delay between diagnosis of neuropathy and initiation of treatment0.32
Results of bivariate analysis after adjustment for histologic result§ 
 Acute neuropathy onset0.007
 Clinical sensorimotor involvement0.19
 Multiple mononeuropathy0.34
 General symptoms0.01
 Increased C-reactive protein level0.43
 Rheumatoid factor0.20
 Monoclonal gammopathy0.40
Multivariate analysis of the best variables related to evolution 
 Acute neuropathy onset0.22
 Clinical sensorimotor involvement0.22
 General symptoms0.20
 Rheumatoid factor0.37
 NMB 
  Lymphocytic vasculitis0.23
  Necrotizing vasculitis on NMB0.01

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Predicting the clinical evolution and response to therapy of patients with primary SS–related peripheral neuropathy is necessary because a more appropriate use of immunosuppressant agents in selected patients might improve the therapeutic efficacy and reduce the toxicity of treatment. Our series is one of the largest analyzing the clinical change in peripheral neuropathy in patients with primary SS according to clinicobiologic and histologic features. Our study is original in using biopsy as an inclusion criterion; other studies were mainly descriptive and could not establish any correlations between subtypes of neuropathic features; clinical, biologic, and histologic findings; and evolution (2–8, 10–12). Moreover, our series is remarkable for the long duration of followup (>6.5 years). We provided insight into how peripheral neuropathic conditions related to primary SS are currently treated in daily rheumatologic practice. Treatment is not codified to date, and various therapies have been used, including corticosteroids (4, 5, 19), immunosuppressant agents (4, 19–21), plasmapheresis (22, 23), D-penicillamine (24), infliximab (25), intravenous immunoglobulins (5, 26–30), and interferon-α therapy (31), often with limited response. This absence of therapeutic guidelines is due in part to the difficulty in evaluating the therapeutic efficacy. This evaluation is made more difficult by the low number of patients, problems in evaluating the clinical response, the necessity of long-term followup because of the slow improvement with therapy, the evaluation of patients with different pathogenic mechanisms (with and without vasculitis), and the absence of randomized controlled studies. Our study tried to take into account most of these limiting factors by determining the precise histopathologic lesions in each patient and by providing a long followup duration.

Because of the retrospective nature of our study, inherent biases should be noted, such as selection bias, which we tried to limit by contacting a large number of clinicians dedicated to autoimmune diseases and primary SS and 3 reference laboratories of neuropathology. The retrospective evaluation of clinical response to therapy could also limit the interpretation of the results.

Because of our inclusion criteria (i.e., requirement of NMB, more frequently performed in case of sensorimotor involvement, in daily rheumatologic practice), only 5 pure sensory ganglionopathy and 1 cranial neuropathy were included, although they represent a common involvement in primary SS–related neuropathy (5, 8, 11). The low prevalence of profound sensory involvement in patients with vasculitis might be related to a selection bias due to the inclusion criteria, since clinicians might perform NMB more frequently in patients with motor involvement than in patients with profound sensory involvement. This might also be related to the fact that the presumed primary affected tissues (i.e., dorsal ganglia) have not been assessed. Last, a different, nonvasculitic, pathogenic mechanism might explain profound sensory involvement in which lymphocytic infiltrates of dorsal ganglia have been reported (7, 12).

Our survey clearly demonstrates that neuropathy due to necrotizing vasculitis may occur in primary SS in the absence of other underlying autoimmune disease. In these 14 patients with necrotizing vasculitis and primary SS, the diagnosis of rheumatoid vasculitis was ruled out by the absence of radiographic erosions and antifilaggrin or anti–cyclic citrullinated peptide antibodies, and no autoimmune disease other than primary SS could be identified. Our series adds 14 new cases to the 19 cases of necrotizing vasculitis in primary SS (including 13 cases with neuropathy) previously described (8, 10, 32–41). Of note, only 9 of the 19 previous cases fulfilled the AECG criteria, whereas all of our 14 patients fulfilled these criteria. Clinical involvement in our patients concerned the peripheral nerve and in 64% of the patients the skin was involved (purpura, ulcers, or livedo), associated with general symptoms (fever, asthenia, or weight loss), but necrotizing vasculitis did not involve the kidney, gastrointestinal tract, or central nervous system, as assessed by clinical and biologic tests. Thus, despite the absence of life-threatening organ involvement, necrotizing vasculitis should be considered in patients with peripheral nerve involvement and general symptoms or skin involvement.

Initial clinical and biologic presentation was significantly associated with the histologic results of NMB. Patients with necrotizing vasculitis or lymphocytic vasculitis more often had acute onset of neuropathy, multiple mononeuropathy and clinical sensorimotor involvement, general symptoms, vascular purpura, increased C-reactive protein level, positivity for rheumatoid factor, hypocomplementemia, and monoclonal gammopathy, and a tendency toward more frequent polyclonal hypergammaglobulinemia, cryoglobulinemia, anti-SSA/SSB antibodies, ANCA, and increased serum β2-microglobulin level than those without vasculitis. No significant clinical or biologic differences could be observed between patients with necrotizing or lymphocytic vasculitis except for the presence of general symptoms and rheumatoid factor. Therefore, clinical and biologic presentation can be helpful to discriminate between patients with and without vasculitis. However, clinical and biologic presentation could not differentiate patients with necrotizing vasculitis from patients with lymphocytic vasculitis.

The association between vasculitis and autoantibodies or increased β2-microglobulin level agrees with the relevance of B cell biomarkers as disease activity markers of primary SS (42). Interestingly, our study describes the clinical evolution of primary SS–related neuropathy after B cell depletion, for which data are very limited in the literature.

Rituximab was used in 6 patients with primary SS–related neuropathy (including 3 patients without vasculitis, 2 with necrotizing vasculitis, and 1 with lymphocytic vasculitis; 4 of these patients had already been reported in a study evaluating tolerance and efficacy of rituximab in primary SS [43]). Three patients showed a good response to rituximab (including 2 with necrotizing vasculitis and 1 without vasculitis), 2 showed a moderate response (including 1 with lymphocytic vasculitis and 1 without vasculitis), and 1 patient without vasculitis showed no response. Interestingly, among the 3 patients with good response, 1 had lymphoma and cryoglobulinemia, 1 had lymphoma without cryoglobulinemia, and 1 had cryoglobulinemia without lymphoma. Two of these 3 patients had multiple mononeuropathy. In addition, the 2 patients with moderate response had cryoglobulinemia (including 1 with lymphoma). Previously, only 2 patients treated successfully with rituximab for peripheral neuropathy associated with lymphoma had already been reported (44, 45). These results suggest the relevance of rituximab in patients with primary SS–related neuropathy, and support the important role of B cells in the pathogenesis of systemic complications in primary SS.

Lastly, the results of this study demonstrate that the histologic results of NMB might represent a prognostic factor. Indeed, immunosuppressant agents (mainly cyclophosphamide) led to a significant improvement of functional status (i.e., the median MRS score) only in patients with necrotizing vasculitis, among whom 71% showed good response to therapy versus 25% in patients with lymphocytic vasculitis and 0% in patients without vasculitis. In univariate analysis, the results of NMB and clinicobiologic variables (acute neuropathy onset, sensorimotor involvement, multiple mononeuropathy, general symptoms, increased C-reactive protein level) were significantly associated with clinical outcome. Interestingly, in multivariate analysis, NMB was the only variable that remained significantly associated with clinical outcome, since only the presence of necrotizing vasculitis was associated with a better prognosis. The results of NMB have not significantly influenced the choice of treatments, because immunosuppressant agents were used as frequently in patients with vasculitis as in patients without vasculitis.

In conclusion, this study, which investigated clinicobiologic presentation, histologic findings, and outcome of primary SS–related peripheral neuropathies, demonstrated that the clinicobiologic features can be helpful to discriminate patients with vasculitis from those without. NMB is necessary to identify the patients with necrotizing vasculitis, who have a better response to immunosuppressive therapy. NMB might therefore have both a diagnostic and prognostic relevance in primary SS–related neuropathy.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

Dr. Mariette had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Terrier, Lacroix, Mariette, Gottenberg.

Acquisition of data. Terrier, Lacroix, Guillevin, Hatron, Dhote, Maillot, Diot, Sarrot-Reynauld, Sordet, Dubourg, Mariette, Gottenberg.

Analysis and interpretation of data. Terrier, Lacroix, Guillevin, Dhote, Maillot, Diot, Sarrot-Reynauld, Mariette, Gottenberg.

Manuscript preparation. Terrier, Lacroix, Mariette, Gottenberg.

Statistical analysis. Terrier, Meyer, Gottenberg.

Acknowledgements

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES

We thank Dr. Anne-Laure Fauchais, Dr. Eric Hachulla (Lille), Dr. Olivier Meyer (Hôpital Bichat, Paris), Dr. Nathalie Costedoat-Chalumeau, Dr. Patrice Cacoub, Dr. Thierry Maisonobe, Dr. François Salachas, Dr. Bertrand Fontaine (Hôpital Pitié-Salpétrière, Paris), Dr. André Kahan, Dr. Achille Aouba (Hôpital Cochin, Paris), Dr. Pascal Priollet (Hôpital Saint-Joseph, Paris), Dr. Robert-Thierry Ghnassia (Chelles), Dr. Hervé Bachelez (Hôpital Saint-Louis, Paris), Dr. Pierre Galanaud (Hôpital Antoine Béclère, Paris), Dr. Rolland Jaussaud (Reims), Dr. Serge Arfi (Fort-de-France), Dr. Jean-Nöel Tillier (Argenteuil), Dr. Xavier Puechal, Dr. Philippe Renou, and Dr. Virak Seng (Le Mans) for their collaboration. We thank Beatrice Ducot (INSERM U569, IFR 69, Le Kremlin-Bicêtre) for performing the multivariate analysis.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. Acknowledgements
  9. REFERENCES
  • 1
    Garcia-Carrasco M, Ramos-Casals M, Rosas J, Pallares L, Calvo-Alen J, Cervera R, et al. Primary Sjögren's syndrome: clinical and immunologic disease patterns in a cohort of 400 patients. Medicine (Baltimore) 2002; 81: 27080.
  • 2
    Alexander EL, Provost TT, Stevens MB, Alexander GE. Neurologic complications of primary Sjögren's syndrome. Medicine (Baltimore) 1982; 61: 24757.
  • 3
    Andonopoulos AP, Lagos G, Drosos AA, Moutsopoulos HM. The spectrum of neurological involvement in Sjögren's syndrome. Br J Rheumatol 1990; 29: 213.
  • 4
    Delalande S, de Seze J, Fauchais AL, Hachulla E, Stojkovic T, Ferriby D, et al. Neurologic manifestations in primary Sjögren's syndrome: a study of 82 patients. Medicine (Baltimore) 2004; 83: 28091.
  • 5
    Font J, Ramos-Casals M, de la Red G, Pou A, Casanova A, Garcia-Carrasco M, et al. Pure sensory neuropathy in primary Sjögren's syndrome: longterm prospective followup and review of the literature. J Rheumatol 2003; 30: 15527.
  • 6
    Gemignani F, Marbini A, Pavesi G, Di Vittorio S, Manganelli P, Cenacchi G, et al. Peripheral neuropathy associated with primary Sjögren's syndrome. J Neurol Neurosurg Psychiatry 1994; 57: 9836.
  • 7
    Grant IA, Hunder GG, Homburger HA, Dyck PJ. Peripheral neuropathy associated with sicca complex. Neurology 1997; 48: 85562.
  • 8
    Kaltreider HB, Talal N. The neuropathy of Sjögren's syndrome: trigeminal nerve involvement. Ann Intern Med 1969; 70: 75162.
  • 9
    Lafitte C. Neuroradiological manifestations of primary Sjögren's syndrome. Rev Neurol (Paris) 2002; 158: 95965. In French.
  • 10
    Mellgren SI, Conn DL, Stevens JC, Dyck PJ. Peripheral neuropathy in primary Sjögren's syndrome. Neurology 1989; 39: 3904.
  • 11
    Mori K, Iijima M, Koike H, Hattori N, Tanaka F, Watanabe H, et al. The wide spectrum of clinical manifestations in Sjögren's syndrome-associated neuropathy. Brain 2005; 128: 251834.
  • 12
    Malinow K, Yannakakis GD, Glusman SM, Edlow DW, Griffin J, Pestronk A, et al. Subacute sensory neuronopathy secondary to dorsal root ganglionitis in primary Sjögren's syndrome. Ann Neurol 1986; 20: 5357.
  • 13
    Murata Y, Maeda K, Kawai H, Terashima T, Okabe H, Kashiwagi A, et al. Antiganglion neuron antibodies correlate with neuropathy in Sjögren's syndrome. Neuroreport 2005; 16: 67781.
  • 14
    Eystathioy T, Chan EK, Takeuchi K, Mahler M, Luft LM, Zochodne DW, et al. Clinical and serological associations of autoantibodies to GW bodies and a novel cytoplasmic autoantigen GW182. J Mol Med 2003; 81: 8118.
  • 15
    Moll JW, Markusse HM, Pijnenburg JJ, Vecht CJ, Henzen-Logmans SC. Antineuronal antibodies in patients with neurologic complications of primary Sjögren's syndrome. Neurology 1993; 43: 257481.
  • 16
    Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al. Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 2002; 61: 5548.
  • 17
    Puechal X, Said G, Hilliquin P, Coste J, Job-Deslandre C, Lacroix C, et al. Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis: a clinicopathologic and prognostic study of thirty-two patients. Arthritis Rheum 1995; 38: 161829.
  • 18
    Authier FJ, Bassez G, Payan C, Guillevin L, Pawlotsky JM, Degos JD, et al. Detection of genomic viral RNA in nerve and muscle of patients with HCV neuropathy. Neurology 2003; 60: 80812.
  • 19
    Griffin JW, Cornblath DR, Alexander E, Campbell J, Low PA, Bird S, et al. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren's syndrome. Ann Neurol 1990; 27: 30415.
  • 20
    Kastrup O, Maschke M, Diener HC. Pulse-cyclophosphamide in the treatment of ataxic sensory and cranial nerve neuropathy associated with Sjögren's syndrome [letter]. Clin Neurol Neurosurg 2005; 107: 4401.
  • 21
    Yamanishi Y, Taooka Y, Mukuzono H, Aoi K, Ishibe Y, Yamana S. Cyclophosphamide-responsive subclinical Sjögren's syndrome in a patient with initial peripheral and central nervous system involvement. Ryumachi 1994; 34: 6338. In Japanese.
  • 22
    Bakchine S, Mas JL, Rottembourg R, Wechsler B, Le Charpentier Y, Derouesne C. Polyneuropathy disclosing primary Gougerot-Sjögren's syndrome: treatment by plasma exchange. Rev Neurol (Paris) 1987; 143: 83940. In French.
  • 23
    Chen WH, Yeh JH, Chiu HC. Plasmapheresis in the treatment of ataxic sensory neuropathy associated with Sjögren's syndrome. Eur Neurol 2001; 45: 2704.
  • 24
    Asahina M, Kuwabara S, Nakajima M, Hattori T. D-penicillamine treatment for chronic sensory ataxic neuropathy associated with Sjögren's syndrome. Neurology 1998; 51: 14513.
  • 25
    Caroyer JM, Manto MU, Steinfeld SD. Severe sensory neuronopathy responsive to infliximab in primary Sjögren's syndrome [letter]. Neurology 2002; 59: 11134.
  • 26
    Molina JA, Benito-Leon J, Bermejo F, Jimenez-Jimenez FJ, Olivan J. Intravenous immunoglobulin therapy in sensory neuropathy associated with Sjögren's syndrome [letter]. J Neurol Neurosurg Psychiatry 1996; 60: 699.
  • 27
    Pascual J, Cid C, Berciano J. High-dose i.v. immunoglobulin for peripheral neuropathy associated with Sjögren's syndrome [letter]. Neurology 1998; 51: 6501.
  • 28
    Takahashi Y, Takata T, Hoshino M, Sakurai M, Kanazawa I. Benefit of IVIG for long-standing ataxic sensory neuronopathy with Sjögren's syndrome. Neurology 2003; 60: 5035.
  • 29
    Levy Y, Uziel Y, Zandman GG, Amital H, Sherer Y, Langevitz P, et al. Intravenous immunoglobulins in peripheral neuropathy associated with vasculitis. Ann Rheum Dis 2003; 62: 12213.
  • 30
    Hebbar M, Hebbar-Savean K, Hachulla E, Brouillard M, Hatron PY, Devulder B. Participation of cryoglobulinaemia in the severe peripheral neuropathies of primary Sjögren's syndrome. Ann Med Interne (Paris) 1995; 146: 2358.
  • 31
    Yamada S, Mori K, Matsuo K, Inukai A, Kawagashira Y, Sobue G. Interferon alpha treatment for Sjögren's syndrome associated neuropathy. J Neurol Neurosurg Psychiatry 2005; 76: 5768.
  • 32
    Peyronnard JM, Charron L, Beaudet F, Couture F. Vasculitic neuropathy in rheumatoid disease and Sjögren's syndrome. Neurology 1982; 32: 83945.
  • 33
    Tsokos M, Lazarou SA, Moutsopoulos HM. Vasculitis in primary Sjögren's syndrome: histologic classification and clinical presentation. Am J Clin Pathol 1987; 88: 2631.
  • 34
    Lahoz Rallo C, Arribas Lopez JR, Arnalich Fernandez F, Monereo Alonso A, Llanos Chavarri MC, Camacho Siles J. Necrotizing vasculitis of the panarteritis nodosa type in a long-course primary Sjögren's syndrome. An Med Interna 1990; 7: 52830. In Spanish.
  • 35
    Sato K, Miyasaka N, Nishioka K, Yamaoka K, Okuda M, Nishido T, et al. Primary Sjögren's syndrome associated with systemic necrotizing vasculitis: a fatal case [letter]. Arthritis Rheum 1987; 30: 7178.
  • 36
    Ramos-Casals M, Anaya JM, Garcia-Carrasco M, Rosas J, Bove A, Claver G, et al. Cutaneous vasculitis in primary Sjögren's syndrome: classification and clinical significance of 52 patients. Medicine (Baltimore) 2004; 83: 96106.
  • 37
    Alexander EL, Craft C, Dorsch C, Moser RL, Provost TT, Alexander GE. Necrotizing arteritis and spinal subarachnoid hemorrhage in Sjögren's syndrome. Ann Neurol 1982; 11: 6325.
  • 38
    Lie JT. Isolated necrotizing and granulomatous vasculitis causing ischemic bowel disease in primary Sjögren's syndrome. J Rheumatol 1995; 22: 23757.
  • 39
    Herreman G, Ferme I, Diebold J, Baviera E, Audouin J, Bazin C, et al. Gougerot-Sjögren's syndrome, periarteritis nodosa, non-Hodgkin's lymphoplasmocytic lymphoma and acquired C4 deficiency. Ann Med Interne (Paris) 1983; 134: 1925. In French.
  • 40
    Bloch KJ, Buchanan WW, Wohl MJ, Bunim JJ. Sjögren's syndrome: a clinical, pathological, and serological study of sixty-two cases. Medicine (Baltimore) 1965; 44: 187231.
  • 41
    Talal N, Bunim JJ. The development of malignant lymphoma in the course of Sjögren's syndrome. Am J Med 1964; 36: 52940.
  • 42
    Gottenberg JE, Busson M, Cohen-Solal J, Lavie F, Abbed K, Kimberly RP, et al. Correlation of serum B lymphocyte stimulator and beta2 microglobulin with autoantibody secretion and systemic involvement in primary Sjögren's syndrome. Ann Rheum Dis 2005; 64: 10505.
  • 43
    Seror R, Sordet C, Guillevin L, Hachulla E, Masson C, Ittah M, et al. Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjögren's syndrome. Ann Rheum Dis 2007; 66: 3517.
  • 44
    Voulgarelis M, Giannouli S, Anagnostou D, Tzioufas AG. Combined therapy with rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) for Sjögren's syndrome-associated B-cell aggressive non-Hodgkin's lymphomas. Rheumatology (Oxford) 2004; 43: 10503.
  • 45
    Voulgarelis M, Giannouli S, Tzioufas AG, Moutsopoulos HM. Long term remission of Sjögren's syndrome associated aggressive B cell non-Hodgkin's lymphomas following administration of combined B cell depletion therapy and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Ann Rheum Dis 2006; 65: 10337.