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Abstract

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

Objective

To compare clinical characteristics and patient-reported outcomes in seropositive versus seronegative primary Sjögren's syndrome (SS) patients and to investigate the effect of serologic status on the prevalence of chronic pain, comorbidity, and health quality.

Methods

Pain severity and neuropathic pain symptoms, comorbidity, and health status were assessed in 108 primary SS patients. Differences between patient groups were assessed by t-test and chi-square test, as well as adjusted pain–affect associations. The effect of predictor variables on pain severity was examined with multivariate regression.

Results

Pain severity was greater (P = 0.003) and physical function (P = 0.023) was reduced in the seronegative patients. Prevalence of neuropathic pain, depression, anxiety, and disability was similar between groups. Chronic pain, defined as daily pain for >3 months, was reported by 65% of seropositive (n = 65) and 75% of seronegative (n = 40) patients. After adjustment for age, sleep quality, and psychological distress, the difference in pain severity between seropositive and seronegative patients remained significant.

Conclusion

Chronic pain is pervasive in both seropositive and seronegative primary SS patients, while pain severity and functional impairment are greater in seronegative patients. Neuropathic pain is equally prevalent and is the predominant pain phenotype in patients with moderate to severe pain. Accurate assessment of pain phenotypes is needed for more effective management of chronic pain in primary SS. The focus of future research should be to standardize assessment of pain and to identify the factors contributing to more severe pain in seronegative patients.


INTRODUCTION

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

Primary Sjögren's syndrome (SS) is a common systemic autoimmune disorder characterized by sicca manifestations and extraglandular organ involvement. Worldwide the prevalence is between 0.1–0.5%, with a female sex predominance of more than 90% ([1]). While the presenting symptoms are usually oral and ocular dryness, some patients present with peripheral neuropathy, as well as a variety of other neurologic features ([2-5]). In a small percentage of patients, the disease slowly evolves into lymphoma ([6, 7]).

Previous studies have emphasized the association of anti-Ro/SSA antibody with the development of extraglandular manifestations such as purpura, lung involvement, nephritis, and risk of lymphoma ([8-11]). According to the American–European Consensus Group (AECG) criteria, patients are classified as primary SS if symptoms and signs of gland dysfunction are documented, and if either specific histopathology (focal lymphocytic infiltration) is demonstrated on biopsy results of minor salivary gland tissue or if serologic tests are positive for either anti-SSA/Ro or anti-SSB/La antibody ([12]). Patients who meet criteria for primary SS but do not have detectable antibody to either anti-Ro/SSA or anti-La/SSB are considered seronegative. The prevalence of anti-Ro/SSA and anti-La/SSB antibodies varies according to the method of detection and referral pattern at the center performing the study ([13]). While seronegative patients have less systemic involvement, the factors contributing to health status specifically in seronegative patients are not well described. There are very limited reported data on whether serologic status modulates functional outcomes or psychological comorbidity in primary SS.

Despite the association of systemic manifestations with positive anti-Ro/SSA, fatigue is a common complaint, influencing health quality in both seropositive and seronegative patients ([10, 14]). As much as 70% of primary SS patients report persistent fatigue ([10, 14-16]). Anxiety and depression are also reported by 25–50% of SS patients ([17-19]). Fibromyalgia (FM), a noninflammatory condition characterized by chronic widespread pain, fatigue, and polysymptomatic distress, can also complicate primary SS ([16]). Predictors of fatigue in primary SS include helplessness, depression, and pain, suggesting that both psychological stressors and behavioral variables, such as coping style and lower perceived personal control, contribute to fatigue in primary SS ([14]). Unfortunately, very little is known regarding the prevalence and impact of chronic pain in primary SS.

The aim of this study was to investigate the clinical characteristics and to compare patient-reported outcomes in seropositive and seronegative primary SS patients. We assessed the following: 1) the prevalence of chronic pain and neuropathic pain, 2) comorbidity, and 3) the effect of serologic status on clinical characteristics. Standardized instruments were used to assess pain severity, neuropathic pain symptoms, fatigue, sleep quality, anxiety, and depression. Patients were asked questions about psychological symptoms, the duration and severity of pain symptoms, and history of physician-diagnosed comorbidity. We hypothesized that psychological distress and pain might be greater in seronegative primary SS patients, whereas objective measures of sicca severity would be similar.

Box 1. Significance & Innovations

  • Chronic pain is reported by more than half of both seronegative and seropositive primary Sjögren's syndrome (SS) patients.
  • Neuropathic pain is equally prevalent in seropositive and seronegative patients and is strongly associated with anxiety and depression.
  • Seronegative primary SS patients report more severe pain and greater impairment in functional status.

PATIENTS AND METHODS

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

Patient population

We evaluated participants in the Biomarkers in Primary Sjögren's Syndrome Project (BioSIPS). BioSIPS is a National Institutes of Health–funded clinical database and biorepository of RNA, DNA, serum saliva, tears, urine, lymphocytes, and minor salivary gland tissue from patients with confirmed primary SS by AECG criteria and healthy matched controls ([12]). The BioSIPS Registry represents a uniquely valuable repository of clinical data and biologic samples obtained from well-characterized primary SS patients and healthy matched controls free of sicca symptoms and autoimmune disease. The Registry includes patients with seronegative primary SS who are under-represented in some large cohorts because minor salivary gland biopsy is not uniformly obtained. Patients are recruited through referrals from the ophthalmology, oral surgery, and rheumatology clinics at the University of Minnesota, as well as through referrals to the Oklahoma Medical Research Foundation Sjögren's Syndrome Research Clinic. Participants are also recruited through newspaper and web site advertisements. While a small number of patients have participated from across the country, the majority of participants reside in either the upper Midwest (approximately 40%) or central US. All participants undergo oral, ocular, and rheumatologic examinations, and relevant tissue and blood samples are collected at a clinic visit. Since 2001, more than 400 confirmed primary SS patients have been enrolled in the BioSIPS Registry.

All patients with sicca symptoms who wish to participate are screened, facilitating recruitment of patients with early disease. Patients undergo a thorough history and physical examination, phlebotomy, and specialized tests of gland function on the day of their research clinic visit. The purpose of the physical examination is to detect signs of unrecognized medical illness, concurrent autoimmune disease other than primary SS, and identification of extraglandular features of SS such as peripheral neuropathy, arthritis, and fatigue. Unstimulated whole salivary flow rate is measured for 15 minutes, and bilateral Schirmer I tear tests are performed according to the AECG criteria. Complete ophthalmologic examinations, including slit lamp examination, vital dye staining (lissamine green), and dilated retinal examination, are also performed on the day of the research clinic visit. Finally, patients have a minor salivary gland biopsy performed by an experienced oral surgeon. The laboratory evaluation includes complete blood count and immunoglobulin level, sedimentation rate, double-stranded DNA, Sm, RNP, rheumatoid factor, and antinuclear antibodies as well as anti-Ro/SSA and anti-La/SSB. All clinical data are reviewed by the study physicians and the principal investigator to determine if patients meet 2002 AECG criteria for primary SS or appear to satisfy criteria for primary SS and an additional autoimmune disorder. Consistency in application of the criteria is assured since only a small number of study physicians are involved in evaluating patients. All participants are informed of the results of the clinical evaluation and provided with a report indicating whether the clinical criteria for primary SS were satisfied.

Tests for anti-Ro/SSA and anti-La/SSB serologies are performed by commercially available enzyme-linked immunosorbent assay kits (Immunovision), precipitin methodology using immunodiffusion (Oklahoma Medical Research Foundation Clinical Immunology Laboratory), and immunoblotting (INNO-LIA; Innogenetics). The care taken in accurately assigning serologic status is of major importance, because descriptive data from existing clinical cohorts may be difficult to interpret due to a high rate of both false-positive and false-negative serologic test results from commercial labs.

Survey data were collected from a sample of 200 BioSIPS participants who satisfied criteria for primary SS. Patients, ages 18–80 years, received an extensive health questionnaire 3–5 years after their initial evaluation in the registry. Patients classified as seronegative primary SS were oversampled to ensure an adequate number of patients for comparison of seropositive and seronegative patient groups. Inclusion criteria were having sufficient English language skills to complete the questionnaire and being age ≥18 years. All participants met AECG criteria for primary SS. The study was approved by the local medical ethics review board.

Study variables

Demographic variables included age, sex, race, and education level. Work and disability status variables were based on patient self-report. Specifically, we asked patients to report the category that best characterized their current work status: paid work, homemaker, student, not employed and not looking for work, retired, or disabled due to health. Objective evaluation of gland function was performed only at the time of enrollment in the registry. All additional data, including updated demographic variables, medical history, and the subjective assessment of the severity of sicca symptoms, were included in the patient survey.

Visual analog scales (VAS) were used to assess the severity of oral sicca symptoms (mean of 12 items related to oral and throat dryness, each rated 0–100) and ocular sicca symptoms (sum of 2 items related to eye dryness, each rated 0–100). VAS scores were also used to assess perceived stress (1 item rated 0–100) and musculoskeletal pain severity (mean of scores for 2 items: joint pain and muscle pain). Questions relating to pain included location of most severe pain and presence of chronic pain, defined as “daily pain for greater than 3 months.” To assess comorbidity, the patients were asked 3 questions: 1) “Have you been diagnosed previously with fibromyalgia, neuropathy, depression or sleep disorder?” 2) “Do you have current symptoms of fibromyalgia, neuropathy, depression, or sleep disorder?” and 3) “Are you currently taking antidepressant medication, medication for anxiety, for sleep disorder, or narcotic pain medication?” Previous research has demonstrated that patients can accurately assess their current and past medical conditions, including comorbidity ([20-22]).

The health questionnaire included multiple instruments to assess pain, fatigue, sleep, and mood. The Brief Pain Inventory (BPI) ([23]) is comprised of 2 components: pain intensity (mean of 4 items, each rated 0–10, where cutoff scores are 0–4 for mild pain, 5–7 for moderate pain, and 8–10 for severe pain) and pain impact (mean of 7 items related to pain interference with activities of daily living, rated 0–10). The Neuropathic Pain Questionnaire (NPQ) is a brief 12-item measure that characterizes pain symptoms as neuropathic or non-neuropathic based on verbal descriptors ([24]). Patients were asked to name the site of pain that was most severe and to rate their pain at that site. Presence or absence of neuropathic pain is determined by an adjusted weighted sum of 12 specific pain scales, each rated from 0–10. The Fatigue Severity Scale (FSS) ([25]) was used to assess the impact of fatigue on daily activities (mean of 9 items, each rated 1–7, with 7 indicating the most severe fatigue and the cutoff score for abnormal fatigue being ≥4). The Pittsburgh Sleep Quality Index (PSQI) ([26]) was used to assess sleep quality (sum of 7 scores, each rated 0–3, where higher scores reflect increased likelihood of a sleep disorder). Psychiatric comorbidity was assessed with the Hospital Anxiety and Depression Scale (HADS; sum of 7 items, each rated 0–3, reflecting generalized anxiety with the cutoff score for anxiety being >10, and 7 items, each rated 0–3, with the cutoff score for depression being >10). The depression scale focuses on loss of interest in life and anhedonia. A composite score for psychological distress is the sum of the HADS anxiety and HADS depression subscale scores ([27]).

Overall health status was assessed with the Short Form 12, version 2 (SF-12v2), health survey ([28]). The SF-12v2 includes 2 summary scores for the physical and mental domains. Scores range from 0–100 for each subscale, with higher scores indicating better functioning. A slightly modified version of the Revised Fibromyalgia Impact Questionnaire (FIQR), the Symptom Impact Questionnaire (SIQR), was included to provide a means to compare the burden of illness in the study population to that previously described in primary FM ([29]). The SIQR is identical to the FIQR, but does not contain any reference to FM. The SIQR total score includes measures of physical impairment, pain, sleep, anxiety, morning stiffness, depression, work status, and overall well-being. The severity of FM is measured by 3 summary domains: overall impact, function, and symptoms, which can be combined to provide a composite score. The SIQR total has a score range of 0–100, with higher scores representing more severe impact.

Statistical analysis

Differences between seropositive and seronegative patients (Tables 1 and 2) were examined using t-tests and chi-square tests for continuous and categorical variables, respectively. Linear and logistic regressions were used to evaluate the adjusted pain–affect associations. Estimates or odds ratios (ORs) along with 95% confidence intervals (95% CIs) were calculated to describe the magnitude of the observed association between case status and specific psychological disorders and comorbidities. The significance threshold was set as P values less than 0.05. All analyses were conducted using R, version 2.12.0 ([30]).

Table 1. Demographics and clinical characteristics in seropositive and seronegative primary SS patients*
VariableSeropositive patientsSeronegative patientsDifference (95% CI)P
No.Mean ± SD or no. (%)No.Mean ± SD or no. (%)
  1. SS = Sjögren's syndrome; 95% CI = 95% confidence interval; WUSF = whole unstimulated salivary flow rate; PSQI = Pittsburgh Sleep Quality Index; VAS = visual analog scale; SF-12 = Short Form 12 health survey; SIQR = Revised Symptom Impact Questionnaire.

  2. a

    Average of left and right eyes.

Total68 40   
Demographics      
Age, years6857.25 ± 12.134061.98 ± 9.23−4.73 (0.61, 8.84)0.025
Female6864 (94.12)4036 (90.00)4.12 (−8.72, 16.95)0.683
White6864 (94.12)4039 (97.50)−3.38 (−12.76, 6.00)0.739
College educated6852 (76.47)3933 (84.62)−8.14 (−25.32, 9.03)0.450
Disabled due to health6112 (19.67)388 (21.05)−1.38 (−19.12, 16.36)1.000
Objective measures      
WUSF positive6646 (69.70)3520 (57.14)12.55 (−9.42, 34.53)0.297
Schirmer's positivea6645 (68.18)3918 (46.15)22.03 (0.73, 43.33)0.043
Symptoms      
Pain severity683.45 ± 2.25404.70 ± 1.92−1.25 (0.44, 2.06)0.003
Pain interference673.33 ± 3.06404.72 ± 2.51−1.39 (0.31, 2.47)0.012
Fatigue severity684.73 ± 1.66405.36 ± 1.31−0.63 (0.06, 1.20)0.031
PSQI score6810.09 ± 5.074010.78 ± 4.14−0.69 (−1.10, 2.47)0.447
Anxiety686.84 ± 4.47406.28 ± 4.030.56 (−2.23, 1.10)0.503
Depression686.24 ± 4.06406.05 ± 3.970.19 (−1.77, 1.40)0.817
Oral (VAS)6453.02 ± 23.023848.06 ± 21.044.96 (−13.84, 3.92)0.270
Ocular (VAS)6469.28 ± 26.453855.71 ± 28.9013.57 (−25.01, −2.13)0.021
Perceived stress603.98 ± 3.56383.58 ± 3.150.40 (−1.77, 0.96)0.558
Quality of life measures      
SF-12 physical score5337.55 ± 10.723832.41 ± 10.215.14 (−9.55, −0.73)0.023
SF-12 mental score5347.18 ± 11.253848.08 ± 9.95−0.90 (−3.54, 5.34)0.688
SIQR score total5935.16 ± 23.863741.05 ± 20.33−5.89 (−3.18, 14.96)0.200
Table 2. Prevalence of chronic pain, neuropathic pain, anxiety, depression, and comorbidity in seropositive and seronegative patients*
VariableSeropositive patientsSeronegative patientsDifference (95% CI)P
No.No. (%)No.No. (%)
  1. 95% CI = 95% confidence interval; SIQR = Revised Symptom Impact Questionnaire.

Total68 40   
Patient-reported outcome      
Fatigue6848 (70.59)4033 (82.50)−11.91 (−29.90, 6.07)0.250
Pain (moderate to severe)6824 (35.29)4027 (67.50)−32.21 (−52.62, −11.79)0.002
Neuropathic pain6825 (36.76)4016 (40.00)−3.24 (−24.24, 17.77)0.897
Chronic pain6542 (64.62)4030 (75.00)−10.38 (−30.16, 9.39)0.370
Anxiety6818 (26.47)407 (17.50)8.97 (−8.78, 26.72)0.406
Depression689 (13.24)405 (12.50)0.74 (−13.04, 14.51)1.000
SIQR score ≥405923 (38.98)3721 (56.76)−17.77 (−40.21, 4.67)0.136
History of comorbidity      
Neuropathy5919 (32.20)3716 (43.24)−11.04 (−33.16, 11.08)0.381
Sleep disorder6319 (30.16)3518 (51.43)−21.27 (−43.56, 1.02)0.062
Fibromyalgia6311 (17.46)4013 (32.50)−15.04 (−34.36, 4.28)0.128
Depression6232 (51.61)3718 (48.65)2.96 (−19.54, 25.47)0.938

RESULTS

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

The survey response rate was 60% overall and was similar in seropositive and seronegative patients. The questionnaire was returned by 123 patients. The clinical and serologic profile of the 40% nonresponders to the survey was similar to the 60% who did respond. Instruments with missing data were scored according to the author's instruction whenever possible. Fifteen respondents who had missing values for the variables used in the multivariate regression model (10 respondents missing NPQ scores, 2 missing BPI scores, 1 missing PSQI scores, and 2 respondents missing both NPQ and BPI scores) were eliminated from the final data set. The demographics of the 15 patients who were excluded did not differ significantly from those patients whose data were analyzed.

Clinical characteristics in seropositive and seronegative primary SS patients

Primary SS patients (n = 108) were classified into seropositive (anti-Ro/SSA positive and/or anti-La/SSB positive) or seronegative (neither anti-Ro/SSA nor anti-La/SSB) (Table 1). Respondents were predominantly female, white, and college educated. Seronegative patients were slightly older (P = 0.025). Seropositive and seronegative patients were otherwise similar in demographics. The proportion of seropositive (20%) and seronegative (21%) patients who reported disability due to health was also similar. Objective measures of salivary gland function were similar; however, more seropositive patients had a positive Schirmer's test (68% of seropositive patients versus 46% of seronegative patients; P = 0.043) and ocular sicca symptoms were rated more severe by seropositive patients (P = 0.021). Fatigue (P = 0.031), pain interference with daily activity (P = 0.012), and average pain intensity (P = 0.003) were greater in the seronegative patients. SF-12 physical function was significantly lower in seronegative patients (P = 0.023).

Pain phenotype, comorbidity, and psychological profiles in seropositive and seronegative patients

Chronic pain (defined as daily pain for >3 months) was reported by a majority of patients in both groups: 65% of the seropositive and 75% of the seronegative patients (P = 0.370). Pain intensity was rated as moderate or severe by 35% of seropositive and 68% of seronegative patients (P = 0.002). The proportion of seropositive patients (37%) and seronegative patients (40%) with neuropathic pain symptoms was similar. There was no difference in the prevalence of abnormal fatigue (FSS score ≥4), anxiety (HADS anxiety score >10), or depression (HADS depression score >10) (Table 2). Thirty-two percent of seropositive patients and 43% of seronegative patients reported a physician diagnosis of neuropathy (P = 0.381). A history of FM was reported by twice as many seronegative patients (33%) as seropositive patients (17%), a difference which did not reach the threshold for significance (P = 0.128). The proportion of patients who had moderate or severe FM impact scores (defined as an SIQR score ≥40) was also higher but not significantly greater in the seronegative patients (57% versus 39%; P = 0.136). There was no significant difference in the use of opioid analgesics, treatment with antidepressants, or in medications used to treat anxiety or sleep disorder (data not shown).

Clinical variables associated with neuropathic pain and predictors of pain severity

Sixty-one percent of patients with neuropathic pain symptoms rated their pain as moderate or severe. The frequency of opioid analgesic use in patients with neuropathic pain symptoms was 32% compared to 13.6% in those without neuropathic pain (P = 0.003). Neuropathic pain symptoms were strongly associated with anxiety (P = 0.005) and with depression (P = 0.002). More severe pain was also associated with worse sleep quality, more severe oral dryness, greater perceived stress, and more anxiety and depression. SF-12 physical and mental domain scores were more impaired in those with moderate or severe pain. Neuropathic pain was predicted by psychological distress (OR 1.12 [95% CI 1.05, 1.21]), but not with serologic status. Serologic status was a significant predictor of overall pain severity in a model adjusted for age, sleep quality, and psychological distress (Table 3).

Table 3. Association of serologic status as a predictor of pain severity or neuropathic pain, adjusted for age, sleep quality, and psychological distress*
AdjustorPain severity outcomeNeuropathic pain outcome
Effect estimate (95% CI)POR (95% CI)P
  1. Estimates for pain severity outcome denote expected pain severity level per unit difference in the adjustor, holding constant all others. Odds ratios (ORs) for neuropathic pain outcome denote multiplicative odds of neuropathic pain vs. non-neuropathic pain for participants per unit difference in the adjustor, holding constant all others. 95% CI = 95% confidence interval.

  2. a

    Psychological distress variable = Hospital Anxiety and Depression Scale composite score.

Seropositive vs. seronegative−1.17 (−1.88, −0.47)0.0010.81 (0.32, 2.01)0.642
Age (per decade)0.17 (−0.13, 0.48)0.2640.98 (0.65, 1.49)0.937
Sleep quality0.12 (0.04, 0.20)0.0051.05 (0.94, 1.17)0.354
Psychological distressa0.12 (0.07, 0.17)< 0.0011.12 (1.04, 1.21)0.003

DISCUSSION

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

Pain is associated with functional limitations and psychological distress in SS, as is the case in other chronic conditions. This study demonstrates several important new observations and raises some interesting questions regarding pain phenotypes in SS. The first important finding was that physical impairment was greater and pain more severe in seronegative primary SS patients. Second, chronic pain was pervasive and reported by the majority of both seropositive and seronegative patients. Neuropathic pain symptoms were frequently reported and equally prevalent in seropositive and seronegative patients.

Recent epidemiologic surveys of the general population have suggested that chronic pain affects 30–50% of the population and that the prevalence of pain of predominantly neuropathic origin is 8% ([31-33]). Neuropathic pain prevalence has not been studied previously, to our knowledge, in the SS population. Neuropathic pain, reported by 37–40% of the patients in the current study, is especially problematic because of its severity, chronicity, and resistance to simple analgesics. The observation that neuropathic pain was equally prevalent in seropositive and seronegative patients is important to note because previous studies have emphasized the occurrence of peripheral nervous system involvement in seropositive patients ([9]). Neuropathic pain, particularly in seronegative patients, may be under-recognized and possibly under-treated.

The precise reason for greater pain severity in the seronegative patients requires more study. Differences in pain perception between seropositive and seronegative patients could have a genetic basis or could reflect an increased tendency for patients with unexplained pain to seek medical care and to be evaluated for SS even when serologic tests for primary SS are negative. Depression and anxiety were associated with more severe pain, but rates of psychiatric comorbidity were similar in seropositive and seronegative patients. The data do suggest that comorbid FM was more common among seronegative patients. Although we did not specifically assess tender points in this survey, higher FM symptom impact scores in the seronegative patients, as well as a history of FM that was twice as high in the seronegative patients, suggest that FM was a factor contributing to the increased pain severity in the seronegative patients.

Incorporating FM assessment into future studies of primary SS should be considered, especially in intervention trials, to control for the effects of FM on patient-reported outcomes. In the UK primary SS registry, there was no difference in fatigue, pain, or dryness in anti-Ro/SSA and anti-La/SSB positive patients compared to seronegative patients; nevertheless, systemic activity was linked to symptoms of fatigue and pain only in seropositive patients ([34]). The prevalence of FM was not reported in that study, and the lack of correlation between systemic activity and patient outcomes in the seronegative patients could reflect overestimation of sicca and fatigue due to the effects of FM.

Previous studies of primary SS have reported wide variation, from 12% to 44%, in rates of FM ([16]). In order to design appropriate interventions for treatment of chronic pain in primary SS, more precise understanding is needed of the factors contributing to the high prevalence of chronic pain in both seropositive and seronegative primary SS. Chronic pain falls into 3 broad categories: 1) nociceptive pain, which occurs as a result of tissue damage in the presence of a functionally intact sensory nervous system, 2) neuropathic pain, which arises when the nervous system is damaged, and 3) chronic pain that occurs without known somatic background. Neuropathic pain assessment tools, such as the NPQ used in this study, are increasingly employed as the first step in the diagnostic examination of persons with chronic pain. Classification of patients into neuropathic and non-neuropathic pain syndromes based on verbal descriptors alone, however, is not sufficient for diagnosis in individual patients, since chronic disorders such as painful neuropathy and FM may in fact share very similar sensory phenomena ([35]).

Nociceptive and neuropathic processes can also coexist and contribute to a mixed clinical picture. Both the neuropathic pain that results from injury or disease to the nervous system and the nociceptive pain that arises from trauma or inflammation can lead to central sensitization, particularly in individuals with high anxiety and emotional distress ([36]). Central sensitization is thought to explain the association recently demonstrated between neuropathic pain and pain arising from severe osteoarthritis of a weight-bearing joint, as well as the association of neuropathic pain symptoms in patients fulfilling criteria for FM ([36, 37]), highlighting the complex mechanisms involved in chronic pain syndromes.

The NPQ can be helpful to identify patients with sensory symptoms. Detailed sensory examination and ancillary tests may be required for accurate diagnosis. Patients with FM and sensory symptoms are especially difficult to distinguish from those patients with only minor deficits on neurologic examination who may have a painful small fiber neuropathy. Nerve conduction studies are insensitive to small fiber neuropathy, hence epidermal nerve fiber biopsy may be necessary to diagnose patients with primary SS who suffer from small fiber neuropathy. While differentiation of neuropathic from pain of non-neuropathic origin may be quite difficult at times, there are still important messages here for clinicians. Pain extent and neuropathic pain symptoms are important clinical variables that should be elicited in the clinical interview.

Neuropathic pain presentations also contribute to delayed diagnosis of primary SS, particularly when patients present with sensory polyneuropathy or polyganglionopathy and mild sicca symptoms. Grant et al reviewed 54 cases of idiopathic peripheral neuropathy associated with sicca symptoms ([38]). Minor salivary gland biopsy results were positive in 73% of cases, whereas antibodies to anti-SSA/Ro and anti-SSB/La were detected in only 10%. Association of non-ataxic sensory neuropathy with older age and negative serologic status has recently been reported in multiple cohorts ([2, 4, 5]). Taken together, these studies suggest that evaluation for ocular and salivary gland involvement and detailed sensory evaluation is necessary, especially in older patients with neuropathic pain symptoms. Older, seronegative SS patients with sensory neuropathy may constitute a unique subset lacking B cell activation markers and having a distinct pathophysiology.

Future research should focus on clarifying the mechanisms and origin of neuropathic pain symptoms underlying the chronic pain experienced by primary SS patients. In 14 patients with chronic neuropathic pain and normal motor examination studied consecutively by Fauchais et al ([39]), small fiber neuropathy was confirmed by reduced epidermal nerve fiber density on skin biopsy findings in all 14 subjects. The prevalence of peripheral nervous system disorders including small fiber neuropathy in primary SS remains uncertain, however, as there is wide variation in the published data. The reported prevalence of polyneuropathy in primary SS ranges from 0% to 56% ([40]). Patients with immune-mediated neuropathies of all types commonly experience moderate or severe neuropathic pain ([41]).

Our study does have several limitations. The results might not be generalizable to men with primary SS or to non–English-speaking primary SS patient populations. Our findings could have been compromised by a selection bias. It is possible that the prevalence of psychological comorbidity, chronic pain, and neuropathic pain was overestimated in this study. However, the demographics of the respondents were similar to that of the total cohort of patients who were classified as primary SS patients in the BioSIPS Registry, and the demographics and prevalence of depression, anxiety, and fatigue were similar to that previously described in the UK primary SS registry ([34]).

This study demonstrates the substantial impact of chronic pain in SS. More precise classification of pain phenotypes is needed to better understand the mechanistic pathways contributing to chronic pain. Earlier recognition and appropriate management of neuropathic pain could improve health outcomes in patients with SS.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS 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. Dr. Segal 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 conception and design. Segal.

Acquisition of data. Segal, Sivils.

Analysis and interpretation of data. Segal, Pogatchnik, Henn, Rudser, Sivils.

REFERENCES

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