ACR 2006 Highlights from Johns Hopkins University

Sjögren’s Syndrome Highlights

Alan Baer, M.D.

Abstract 1678: Autoantibodies Against Aquaporins in primary Sjögren’s Syndrome

Authors:

Nikolay P. Nikolov, Peter D. Burbelo, Hannah P. Leahy, Sandra Groot, Maria I. Alba, James N. Baraniuk, Michael J. Iadarola, Gabor G. Illei.

Background:

Aquaporins (AQP) are a family of water-specific membrane channel proteins which mediate membrane water transport in many organs. AQP-1 and AQP-5 are expressed in the salivary and lacrimal gland tissues and play an important role in their secretory function. AQP-5 has been observed to be localized predominantly at the basal membrane of acinar cells from Sjogren’s syndrome (SS) patients, in contrast to its predominant localization at the apical membrane of acinar cells from normal individuals. AQP-4 is expressed primarily in the central nervous system. In this study, the presence of autoantibodies to AQP-1 and AQP-5 in SS patients was sought. Such autoantibodies, if detected, could be postulated to contribute to the decreased exocrine function in pSS. Antibodies to AQP-4 were also sought since autoantibodies against AQP-4 have been linked to neuromyelitis optica.

Methods:

72 sera from 54 primary SS patients and 25 normal volunteers were tested for autoantibodies against aquaporin-1, -4 and -5 with the Luciferase Immunoprecipitation System (LIPS). Autoantibody profiles were correlated with laboratory and clinical parameters.

Results:

 Autoantibodies to AQP-1 and AQP-5 were not detected in either the SS or control samples. In contrast, 9/72 (13%) of the SS samples [from 7/54 (13%) patients] had positive anti-AQP-4 antibody titers. LIPS testing of an additional deletion mutant of AQP-4, missing the N-terminal 53 amino acids, failed to show immunoreactivity, suggesting that many of the anti-AQP-4 antibodies might be due to conformational epitopes. Anti-AQP-4 autoantibody titers observed in the SS samples were not simply a reflection of indiscriminate polyclonal B cell activation, since 3/9 anti-AQP-4 positive samples were found in subjects with no autoantibodies to La and Ro52. 5/7 of the anti-AQP-4 positive patients had neurologic involvement: 3 had peripheral neuropathy, 1 trigeminal neuralgia and 1 asymptomatic white matter lesions on a brain MRI.

Conclusion:

These findings provide the first evidence that autoantibodies against aquaporin-4 can be found in primary SS, primarily in patients with neurologic manifestations. This observation raises the possibility that anti-AQP4, which is thought to be highly specific for neuromyelitis optica and longitudinal transverse myelitis, may have a role in the neurologic manifestations of SS and potentially other autoimmune disorders. Antibodies against AQP-1 and 5 do not appear to contribute to the exocrine dysfunction in primary SS.

Editorial Comment:

Demyelinating disease of the central and peripheral nervous systems has been associated with Sjogren’s syndrome and other autoimmune disorders, such as systemic lupus erythematosus. The pathophysiologic basis for this link has not been elucidated. The finding of aquaporin-4 autoantibodies in patients with Sjogren’s syndrome and their correlation with neurologic manifestations is a potentially seminal observation but needs to be confirmed in larger studies.

Abstract 1680: Early Small Fiber Sensory Involvement In Asymptomatic Patients With Primary Sjögren Syndrome: A Follow-up Study

Authors:

Sara Bonazza, Marcello Govoni, Grazia Devigili, Alfonso Massara, Valeria Tugnoli, Ilaria Casetta, Maria Rosaria Tola, Giuseppe Lauria, Enrico Granieri, Francesco Trotta.

Background:

Sensory neuropathy is the most common form of peripheral nerve involvement in Sjogren’s syndrome (SS). This study sought to determine whether small sensory fiber involvement could be detected among primary Sjögren syndrome patients who lacked any symptoms of a peripheral neuropathy and whether such involvement correlated with the subsequent development of a symptomatic sensory neuropathy.

Methods:

Ten patients with primary SS without symptoms suggestive for neuropathic involvement were prospectively evaluated. Other causes known to be associated with small fiber sensory neuropathy (SFSN) were excluded. Small fiber function and morphology were evaluated at baseline and 16.5 months later using: 1) quantitative sensory tests (QST) to determine sensory thresholds to warm and cold stimuli; 2) cutaneous blood flow (CBF) measured by laser Doppler flowmetry (LDF) at the level of the foot, distal leg and proximal thigh; 3) skin biopsies performed at the proximal thigh and distal leg. Epidermal small nerve fiber density was also assessed in skin biopsies from 20 volunteer healthy control subjects.

Results:

10 pts (9 F/1 M, mean age 51.7 ± 14 yrs, mean disease duration 8 yrs) were evaluated. At baseline, QST were abnormal in 8 of 10 (80%) with most pts demonstrating cold allodynia (6), followed by increased warm sensation (4), increased warm thresholds (3), and heat allodynia (1). Skin CBF was pathologic in 20%. Intraepidermal nerve fiber (IENF) density was reduced relative to the control subjects in 9 of 10 pts, in 8 with no length-dependent pattern, in one with length-dependent pattern. At the time of the follow-up evaluation (mean time 16.5 months), 9 of 10 patients developed symptoms suggestive of SFSN, primarily pinprick hypoesthesia.
Conclusions: This study demonstrated the frequent presence of impairment of small sensory fibers in primary SS pts, despite the lack of sensory symptoms. A multimodal approach is necessary to detect subclinical small fiber involvement which may predict progression to a symptomatic phase and to a more diffuse neuropathy or neuronopathy.

Editorial Comment:

Measurement of sensory thresholds in the skin is dependent on the cooperation of the patient and is subject to a variety of psychophysical factors. Thus, the investigators should have also performed quantitative sensory testing on age- and sex-matched healthy control subjects in order to control for the potential influence of these psychophysical factors. Similarly, the skin biopsies from the Sjogren’s syndrome patients and the controls should have been read in a blinded fashion to eliminate any bias.

Abstract 1684: SICCA-International Sjögren’s Syndrome Registry: Two Year Follow-up Analyses and Elucidation of Two Keratoconjunctivitis Sicca Subtypes

Authors:

T. Daniels1, J.S. Greenspan1, S.J. Challacombe2, D. Cox1, L.A. Criswell1, Y. deSouza1, Y. Dong3, D. Greenspan1, A. Heidenreich4, S. Hamann5, R. Jordan1, K. Kitagawa6, H. Lanfranchi4, G. Larkin2, K. Sack1, M. Schiodt5, C. Shiboski1, S. Shiboski1, S. Sugai6, H. Umehara6, J. Whitcher1, A. Wu1, S. Zhang3.

Background:

The Sjögren’s International Collaborative Clinical Alliance (SICCA) is an ongoing prospective study whose goals are to establish an international Sjogren’s syndrome (SS) registry, develop standardized classification criteria, collect and store clinical data and biospecimens, and provide these resources to researchers for future studies of SS. The investigators report the baseline enrollment and preliminary two year follow-up examination data of the SICCA cohort and elucidate two specific types of keratoconjunctivitis sicca (KCS).

Methods:

In the SICCA study, ocular, oral-salivary, and rheumatologic examinations are protocol-directed at its six international sites, as are all collection procedures for nine types of biospecimens from participants suspected of having SS. Defined participants are recalled after two years to repeat all observations. KCS is diagnosed and graded by the presence and severity of ocular surface staining with lissamine green and fluorescein, from which two groups with KCS were compared: those with anti-SS-A/B antibodies, significant focal lymphocytic sialadenitis (FLS) or both (SS-KCS) to those who have KCS-only.

Results:

To date, 1169 participants have completed baseline and 128 two year follow-up examinations. Over the follow-up period, there was no measurable overall progression or regression of most phenotypic SS-related characteristics except in two individuals (out of 62 follow-up biopsies) whose labial salivary glands progressed significantly from FLS to follicular lymphocytic proliferation or MALT lymphoma. Compared with SS-KCS (n=374), those with KCS-only (n=249) had normal or low levels of serum autoantibodies (RF, ANA titer, IgG), higher ocular physiologic tests (unanesthetized Schirmer, tear break-up time), more frequent use of anticholinergic drugs (all at p<.0001) and were older (p=.001).

Conclusions:

These initial and preliminary longitudinal data reveal slowly progressing disease in most patients but rapid transition to a more severe phenotype in a minority of patients. KCS-only cases may represent a distinct entity of sero-negative KCS that is generally less severe than SS-KCS and may not progress into SS-KCS.

Editorial Comment:

Sjogren’s syndrome is only one potential cause of dryness of the eyes and/or mouth. These preliminary data from the SICCA study highlight the presence of a substantial subset of patients with keratoconjunctivitis sicca who lack SS-A or SS-B antibodies and focal lymphocytic sialoadenitis on lip biopsy. These patients tend to be older, use anticholinergic drugs more often, and have less severe measures of ocular dryness than patients with Sjogren’s syndrome. Such patients might have an early form of Sjogren’s syndrome or have a distinct pathophysiologic entity. With the longitudinal follow-up of these patients in the SICCA cohort, parameters that will distinguish these two possibilities should become known. Although serial labial gland biopsies are rarely performed, the SICCA study has also highlighted their potential utility with the identification of two patients (out of 60 with serial biopsies) in whom focal lymphocytic sialoadenitis progressed over a two-year time period to lymphoproliferative disorders.

Abstract 713: Rituximab Treatment In Primary Sjögren’s Syndrome: A Double-blind Placebo Controlled Trial

Authors:

Jiska M. Meijer, Arjan Vissink, Petra M. Meiners, Fred KL Spijkervet, Cees GM Kallenberg, Hendrika Bootsma.

Background:

No therapy has proven efficacy in reversing salivary or lacrimal gland inflammation and secondarily improving the sicca manifestations of Sjogren’s syndrome. Rituximab, a monoclonal antibody that depletes CD20-positive B cells, has been shown in small clinical series to be effective in controlling the extraglandular manifestations of Sjogren’s syndrome. Its failure to improve salivary or lacrimal gland function in studies to date may relate to the inclusion of patients with more advanced Sjogren’s disease and thus with more likely salivary gland damage. In this double-blind placebo controlled trial of rituximab therapy of Sjogren’s syndrome, patients with a normal baseline level of whole saliva excretion were studied.

Methods:

Patients with active primary SS, according to the revised European - U.S. criteria, and stimulated whole saliva secretion ≥ 0.15 ml/min were treated with either rituximab (2 iv infusions of 1000 mg) or placebo on days 1 and 15. Patients were stratified for disease duration (more or less than 4 yrs) and randomised in a 2:1 ratio (rituximab:placebo). All patients were pre-treated with 100 mg intravenous methylprednisolone, and received a tapering dosage of oral prednisolone (60-15 mg/day in 5 days) to minimize the incidence of infusion reactions, HACA’s and serum sickness. The primary end-point at 24 weeks was the level of secretion of stimulated whole saliva. Secondary end-points were B-cell counts, IgM-rheumatoid factor level, level of fatigue (Multidimensional Fatigue Inventory; MFI) and sensation of oral dryness (Visual Analogue Scale; VAS).

Results:

Thirty patients (29 female) were randomized. Mean age was 43±11 and 43±17 yrs and disease duration was 63±50 and 67±63 months in the rituximab and in the placebo group, respectively. Disease duration was less than 4 years in 55% of the rituximab group versus 60% in the placebo group. Salivary secretion (ml/min) improved in the rituximab group (baseline: mean 0.77±0.69, week 12: mean 0.87±0.87) and decreased in the placebo group (baseline: mean 0.45±0.25, week 12: mean 0.28±0.17). B cells were completely depleted in all patients treated with rituximab after the first infusion IgM-rheumatoid factor levels (U/l) decreased in the rituximab group (baseline: mean 102±79, week 24: mean 37±26) and slightly increased in the placebo group (baseline: mean 220±244, week 24: mean 258±260). VAS score for oral dryness improved in the rituximab group (baseline: mean 55±28, week 24: mean 39±27) and slightly deteriorated in the placebo group (baseline: mean 59±28, week 24: mean 64±27). MFI score for general fatigue improved in both groups, the largest improvement was observed in rituximab-treated patients with disease duration less than 4 years (baseline: mean 16±5, week 24: mean 11±3).

Conclusions:

Based on these interim results rituximab seems to be an effective treatment for primary Sjögren syndrome.

Editorial Comment:

These preliminary results suggest that rituximab may improve whole saliva excretion in Sjogren’s patients with less advanced disease who have some preservation of salivary function at baseline. The results described above are those at 24 weeks. It will be important to have the 48 week data and determine whether the outcome measures are statistically significant.

Abstract 1686: Utility of Salivary Scintigraphy to Monitor Treatment of Sjögren’s Syndrome (SS) Using Rituximab

Authors:

Frederick B. Vivino, Geming Li, Phillip L. Cohen, George A. Hermann, Abass Alavi.

Background:

Salivary scintigraphy provides measures of salivary gland function and may be used to provide objective evidence of the salivary component of Sjogren’s syndrome. Its utility is limited by wide variability in reported diagnostic sensitivity and lack of diagnostic specificity for Sjogren’s syndrome.  This study sought to determine whether salivary scintigraphy would have value in monitoring changes in salivary gland function of patients enrolled in a clinical trial of rituximab therapy.

Methods:

Six patients with systemic or extraglandular manifestations of primary SS received two 1000 mg doses of IV rituximab 2 weeks apart in a 12 month open label study. All patients underwent Tc-99m pertechnetate salivary scintigraphy at baseline, 6 and 12 months post therapy. A gustatory stimulus (lemon drops) was administered during the final 15 minutes to examine stimulated function. Trapping/uptake (TU) and discharge (DC) functions were separately evaluated in each salivary gland using background corrected time-activity curves graded 1-4 (1=normal). Progressively flattened TU or defective spontaneous, stimulated or total DC function was deemed abnormal.

Results:

All primary SS patients exhibited abnormal baseline salivary scintigraphy with one or more abnormalities in uptake and/or discharge in at least one major salivary gland; two patients had no demonstrable TU or DC function in any major salivary gland. Mean total uptake scores at 6 months post rituximab improved in 3 of 4 patients with residual salivary gland function; scores changed from 9.7 (baseline) to 9.0 (post treatment). At 6 months changes in uptake function were noted in 8 salivary glands (4 parotids, 4 submandibulars) with improvement in 5 glands and worsening scores in 3. At 12 months post rituximab, improvement compared to baseline persisted in 4 major salivary glands, reverted to pretreatment baseline in 4 and worsened in one (mean uptake score 8.6). No significant changes in DC function were observed over the course of the study.

Conclusions:

Salivary scintigraphy with dynamic sequential imaging of major salivary glands may be a useful outcome measure to monitor response to therapy in SS with rituximab or other treatments.

Editorial Comment:

There is a critical need for reliable outcome measures that can be used to assess the potential benefits of various treatment modalities for the sicca component of Sjogren’s syndrome. Salivary scintigraphy may be potentially useful, since it allows measurement of different aspects of salivary gland function and can be repeated serially over time. As with DEXA bone densitometry and similar diagnostic tests, salivary scintigraphy needs to be validated with measurement of its reproducibility and its intra- and inter-observer agreement. For example, it is not known how much variability there may be in the test when performed repeatedly over a relatively short period of time without any therapeutic intervention. Such information is critical for the assessment of small changes in salivary gland function observed over time.

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