今日の臨床サポート

シェーグレン症候群

著者: 狩野俊和 国立国際医療研究センター国府台病院 リウマチ膠原病科

監修: 金子礼志 国立国際医療研究センター 膠原病科

著者校正済:2021/12/08
現在監修レビュー中
参考ガイドライン:
  1. 厚生労働科学研究費補助金難治性疾患等政策研究事業 自己免疫疾患に関する調査研究班:シェーグレン症候群診療ガイドライン2017年版
  1. 日本シェーグレン症候群学会:シェーグレン症候群の診断と治療マニュアル改訂第3版
  1. EULAR recommendations for the management of Sjögren’s syndrome with topical and systemic therapies
患者向け説明資料

概要・推奨   

  1. シェーグレン症候群は唾液腺炎、涙腺炎を主体として、様々な自己抗体を伴う自己免疫疾患である。
  1. 他の膠原病の合併がみられない一次性シェーグレン症候群と合併する膠原病がある二次性シェーグレン症候群に分けられる。一次性シェーグレン症候群は唾液腺・涙腺などの腺症状のみの腺型と全身臓器に病変が及ぶ線外型とに分類される。診断は厚生省改訂診断基準(1999年)が主に使われていて、難病申請の基準にもなっている。腺症状の治療は対症療法が主体であるが、腺外症状に対してはステロイドや免疫抑制剤が試みられるが確立した治療法はない。
  1. 乾燥症状に関しては治癒は困難であるため、症状の緩和を目指す。全身性合併症で高い活動性を持つ場合はステロイド、免疫抑制剤、生物学的製剤の使用が検討される。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
狩野俊和 : 特に申告事項無し[2022年]
監修:金子礼志 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 主にシェーグレン症候群診療ガイドライン2017年度版を取り入れて変更、追記した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. シェーグレン症候群はリンパ球が涙腺や唾液腺に浸潤することにより眼球乾燥や口腔乾燥が生じる疾患であり、診断基準を参考にして診断する。
  1. しばしば他の膠原病、甲状腺疾患に合併し症状が乏しいことも多いので、これらの疾患の診断時には合併がないかを検討する必要がある。
  1. 50歳代の女性が最多であるが、あらゆる年齢層に広く分布している。男女比は1:14で、女性の割合が自己免疫疾患のなかでも最も高い。
  1. 疾患そのものや乾燥症状に対しては積極的な治療はなく、対症療法が主体である。特殊な合併症の場合にのみ、ステロイドなどの免疫抑制療法を考慮する。
  1. 疾患の治癒は難しい。乾燥症状は年余にわたり変化が認められないことが多いが、ゆっくりと進行することもある。3~5%の患者に発生する悪性リンパ腫は予後を左右する。
  1. シェーグレン症候群は、指定難病であり、ESSDAIにて重症(5点以上)などの場合は申請し認定されると保険料の自己負担分の一部が公費負担として助成される<図表>。([平成27年1月施行])
  1.  難病法に基づく医療費助成制度 
 
問診・診察のポイント  
  1. 症状に乏しいことも多いので、積極的な問診を行わないと乾燥症状を確認できないこともよくある。「目がゴロゴロしないか?」「口が乾くまたはパサパサしないか?」「虫歯が増えたか?」を確認する。

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文献 

Vasiliki-Kalliopi Bournia, Panayiotis G Vlachoyiannopoulos
Subgroups of Sjögren syndrome patients according to serological profiles.
J Autoimmun. 2012 Aug;39(1-2):15-26. doi: 10.1016/j.jaut.2012.03.001. Epub 2012 May 8.
Abstract/Text Sjögren Syndrome (SS) is a systemic, autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands. Different clinical associations have been described for each of the diverse autoantibodies found in SS patients. Antibodies directed against the Ro/La ribonucleoprotein complexes have been correlated with younger age, more severe dysfunction of the exocrine glands and a higher prevalence of extraglandular manifestations. Anti-nuclear antibodies and rheumatoid factors have been associated to extraglandular manifestations and an active immunological profile, while cryoglobulins are markers of more severe disease and correlate to lymphoma development and death. Antibodies to cyclic citrullinated peptides are scarce in SS and have been linked in some cases to the development of non-erosive arthritis. Furthermore, the presence of anti-mitochondrial antibodies and anti-smooth muscle antibodies in the sera of primary SS patients is considered indicative of primary biliary cirrhosis and autoimmune hepatitis, respectively. In addition, anti-centromere antibodies have been associated with a clinical phenotype intermediate between primary SS and systemic sclerosis, while antibodies against carbonic anhydrase have been related to renal tubular acidosis. Finally, an association of anti-muscarinic antibodies with cytopenias and a higher disease activity has also been described in primary SS. In conclusion, although not all of the above mentioned antibodies are useful for predicting distinct patient subgroups in SS, knowledge of the clinical associations of the different autoantibody specificities encountered in SS can advance our understanding of the disease and improve patient management.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22575069
Masako Tsukamoto, Katsuya Suzuki, Tsutomu Takeuchi
Clinical and Immunological Features of Anti-centromere Antibody-Positive Primary Sjögren's Syndrome.
Rheumatol Ther. 2018 Dec;5(2):499-505. doi: 10.1007/s40744-018-0126-2. Epub 2018 Sep 25.
Abstract/Text INTRODUCTION: Anti-centromere antibody (ACA)-positive Sjögren's syndrome (SS) is considered a subtype of SS. ACA-positive SS patients display several features, such as Raynaud's phenomenon, sclerodactyly, and extraglandular dysfunction. However, information on the features of ACA-positive SS is insufficient and the clinical significance of ACA in SS has not been fully established. The aim of this study was to clarify the features of ACA-positive SS.
METHODS: All patients with primary SS who visited our hospital were enrolled. Clinical information and immunological tests were collected and statistically analyzed.
RESULTS: A total of 585 patients were classified as having primary SS. They were divided into four groups by serum ACA and anti-SS-A antibody status as follows: 22 had ACA only (ACA alone), 464 had anti-SS-A antibodies only (SS-A alone), 26 had both ACA and anti-SS-A antibodies (double-positive), and 73 had neither ACA nor anti-SS-A antibodies (seronegative). The proportion of patients with dryness did not differ between the four groups. The proportion of patients with Raynaud's phenomenon or sclerodactyly was higher in the ACA alone and double-positive groups. The proportion of patients with increased serum IgG or IgA was 0 and 5% in the ACA alone group, 61 and 20% in the SS-A alone group, 52 and 28% in the double-positive group, and 20 and 4% in the seronegative group (p < 0.01 and p < 0.01), respectively. The proportion of patients with leukocytopenia was significantly lower in the SS-A-negative group than in the other groups.
CONCLUSIONS: Our study identified characteristics of ACA-positive SS patients that differ from those of anti-SS-A antibody-positive SS patients.

PMID 30255483
Raphaèle Seror, Philippe Ravaud, Simon J Bowman, Gabriel Baron, Athanasios Tzioufas, Elke Theander, Jacques-Eric Gottenberg, Hendrika Bootsma, Xavier Mariette, Claudio Vitali, EULAR Sjögren's Task Force
EULAR Sjogren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren's syndrome.
Ann Rheum Dis. 2010 Jun;69(6):1103-9. doi: 10.1136/ard.2009.110619. Epub 2009 Jun 28.
Abstract/Text OBJECTIVE: To develop a disease activity index for patients with primary Sjögren's syndrome (SS): the European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI).
METHODS: Thirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific 'domains' contributing to disease activity. For each domain, features of disease activity were classified in three or four levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0-10 physician global assessment (PhGA) scale, each expert scored the disease activity of five patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain.
RESULTS: All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p<0.001). Compared with 57 (59.4%) of the real patient profiles, 468 (66.7%) of the realistic vignettes were considered likely or very likely to be true.
CONCLUSIONS: The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardised evaluation of primary SS should facilitate clinical research and be helpful as an outcome measure in clinical trials.

PMID 19561361
Abstract/Text BACKGROUND/AIMS: Hyaluronan (sodium hyaluronate) has been shown to confer objective and subjective improvement in patients with dry eye syndrome. This study compared the efficacy and safety of a 0.1% solution of hyaluronan with 0.9% saline, when administered topically to the eye, in the treatment of symptoms of severe dry eye syndrome.
METHODS: A randomised, double blind, crossover clinical trial in which subjects were randomised to receive either hyaluronan or saline, applied as one or two drops to the eye, three or four times a day or as required. After 28 days' treatment, subjects crossed over to the other study medication for a further 28 days' treatment.
RESULTS: 70 subjects were included in the analyses of efficacy and significant improvements in Schirmer's score (p=0.0006) and rose bengal staining score (p=0.0001) were observed during treatment with hyaluronan. In a subjective assessment of the effectiveness of two treatments, a majority of subjects felt that hyaluronan was more effective than saline in alleviating the symptoms of burning and grittiness (p<0.001). No adverse events attributable to hyaluronan treatment were reported.
CONCLUSION: The study demonstrates a clear benefit of hyaluronan over saline, in both subjective and objective assessments of dry eye syndrome. Hyaluronan was shown to be well tolerated.

PMID 10502570
P Aragona, G Di Stefano, F Ferreri, R Spinella, A Stilo
Sodium hyaluronate eye drops of different osmolarity for the treatment of dry eye in Sjögren's syndrome patients.
Br J Ophthalmol. 2002 Aug;86(8):879-84.
Abstract/Text AIM: To study the effect of the treatment of dry eye in Sjögren's syndrome patients with hypotonic or isotonic hyaluronate eye drops.
METHODS: 40 Sjögren's syndrome patients were divided in two groups and treated as follows: group 1 with hypotonic (150 mOsm/l) 0.4% hyaluronate eye drops; group 2 with isotonic 0.4% hyaluronate eye drops. The eye drops were instilled six times a day for 90 days. Grading of subjective symptoms, break up time (BUT), corneal fluorescein staining, conjunctival rose bengal staining, Schirmer's I test, and conjunctival impression cytology were carried out at 0 and 15, 30, 90 days from the beginning of the study. Patients were examined in a blind fashion. For the statistical analysis the Student's t test, Mann-Whitney U test, and chi(2) test were performed.
RESULTS: Symptoms were statistically significantly improved at day 15 in both groups but group 1 patients had a global score statistically significantly better group 2 (p=0.02). At day 15 group 1 patients had an improvement from baseline values of BUT (p=0.003), fluorescein, and rose bengal score (p=0.000001 and p=0.0004 respectively). Group 2 patients had, at day 15, an improvement of BUT and fluorescein score compared to baseline values (p=0.05 and p=0.0001 respectively). A comparison between the two groups showed better results for group 1 patients at day 15 for rose bengal stain (p=0.01) and for BUT (p=0.05) and fluorescein score (p=0.0003) at day 90. The conjunctival impression cytology showed that group 1 had a statistically significant better total score than group 2 starting from day 15 and lasting throughout the study (p<0.02). Also group 2 patients showed an improvement from baseline values starting from day 30 (p=0.000005).
CONCLUSION: Hyaluronate eye drops are useful for treating severe dry eye in Sjögren's syndrome patients. The use of a formulation with pronounced hypotonicity showed better effects on corneoconjunctival epithelium than the isotonic solution.

PMID 12140209
Pasquale Aragona, Vincenzo Papa, Antonio Micali, Marcello Santocono, Giovanni Milazzo
Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye.
Br J Ophthalmol. 2002 Feb;86(2):181-4.
Abstract/Text BACKGROUND/AIMS: Several studies have reported that sodium hyaluronate is able to improve both symptoms and signs in patients with dry eye but none have demonstrated an improvement of conjunctival epithelial cell abnormalities of the ocular surface. The aim of this study was to explore the effect of sodium hyaluronate-containing eye drops on the ocular surface of patients with dry eye during long term treatment.
METHODS: A randomised double blind study was undertaken in 86 patients with medium to severe dry eye (that is, rose bengal and/or fluorescein test score of at least 3, tear film break up time <10 seconds, or Schirmer's test <5.5 mm). Patients were treated with either preservative-free sodium hyaluronate or saline for 3 months at a dose of one drop 4-8 times a day. Bulbar impression cytology, slit lamp examinations, and subjective symptoms were evaluated after 1, 2, and 3 months. Impression cytology was considered the primary efficacy parameter of the study.
RESULTS: The efficacy analysis was performed on a total of 44 patients who were able to fully adhere to the protocol. After 3 months of treatment sodium hyaluronate improved impression cytology score (p = 0.024 v baseline). At the same time also the difference with respect to placebo was statistically significant (p = 0.036). Study medication was well tolerated and no treatment related adverse events occurred during the study.
CONCLUSIONS: Sodium hyaluronate may effectively improve ocular surface damage associated with dry eye syndrome.

PMID 11815344
Abstract/Text AIMS: To assess the safety and performance of a 0.1% (w/v) solution of sodium hyaluronate (HA, Fermavisc, in the alleviation of symptoms of severe dry eye in comparison with a 1.4% (w/v) solution of polyvinyl alcohol.
METHODS: A randomised, crossover, multicentre study carried out at eight centres in the UK. Eligible patients giving written informed consent were randomised to the order in which they would receive the two study products. Each treatment period lasted for 4 weeks, then the patient crossed over to the other study product. Symptoms of burning and grittiness were assessed by visual analogue scale (VAS) at each study visit and other objective clinical assessments of ocular structure and function were carried out at baseline and the end of each treatment period.
RESULTS: Thirty-nine patients were entered into the study and 32 completed both treatment periods and were included in the statistical analyses. A significant improvement in the patients' VAS assessment of burning was seen after treatment with HA (P = 0.03, 95% Confidence Interval: -23.5 to -1.1). This treatment also resulted in a significantly lower rose bengal staining score (P = 0.04, 95% Confidence Interval: -1.62 to -0.05 for the right eye).
CONCLUSION: The results show a significant clinical benefit in terms of relief of the symptom of burning when HA is applied topically to the eye three or four times per day or as required. HA also appears to have a protective effect on the corneal epithelium, as shown by a reduction in the level of staining of corneal epithelial cells by rose bengal. This study confirms that Fermavisc is a safe and effective product for use in the alleviation of symptoms of severe dry eye syndrome.

PMID 12194076
Manuel Ramos-Casals, Pilar Brito-Zerón, Antoni Sisó-Almirall, Xavier Bosch, Athanasios G Tzioufas
Topical and systemic medications for the treatment of primary Sjögren's syndrome.
Nat Rev Rheumatol. 2012 May 1;8(7):399-411. doi: 10.1038/nrrheum.2012.53. Epub 2012 May 1.
Abstract/Text The treatment of primary Sjögren's syndrome (SS) is based principally on the management of sicca features and systemic manifestations. Sicca manifestations are treated symptomatically through administration of topical therapies, such as saliva substitutes and artificial tears; in patients with residual salivary gland function, stimulation of salivary flow with a sialogogue is the therapy of choice. The management of extraglandular features must be tailored to the specific organ or organs involved; however, limited data have been obtained from controlled trials in SS to guide the treatment of systemic symptoms using therapies including antimalarials, glucocorticoids, immunosuppressive drugs and biologic agents. Nevertheless, randomised controlled trials of biologic agents that target molecules and receptors involved in the aetiopathogenesis of primary SS have initiated a new era in the therapeutic management of the disease, although the potential risks and benefits of these agents must be carefully considered. In this Review, we analyse the evidence regarding the efficacy of the therapeutic agents currently available to treat the manifestations of SS. On the basis of this evidence, we provide guidance on the use of these agents in different clinical scenarios.

PMID 22549247
Gary N Foulks
Treatment of dry eye disease by the non-ophthalmologist.
Rheum Dis Clin North Am. 2008 Nov;34(4):987-1000, x. doi: 10.1016/j.rdc.2008.08.008.
Abstract/Text Physicians caring for patients who have Sjögren's syndrome often face a particularly difficult task in managing the dry eye that occurs with this disease. The discomfort produced by the condition and the fluctuation of vision attendant to tear film instability are often the most annoying of the clinical symptoms. The understanding of dry eye disease in both its clinical expression and underlying etiopathology has expanded over the past 10 years with implications for management and therapy. The array of potential treatments both topical and systemic has evolved to provide a much more targeted and effective arsenal from which the clinician may choose.

PMID 18984417
Manuel Ramos-Casals, Athanasios G Tzioufas, John H Stone, Antoni Sisó, Xavier Bosch
Treatment of primary Sjögren syndrome: a systematic review.
JAMA. 2010 Jul 28;304(4):452-60. doi: 10.1001/jama.2010.1014.
Abstract/Text CONTEXT: A variety of topical and systemic drugs are available to treat primary Sjögren syndrome, although no evidence-based therapeutic guidelines are currently available.
OBJECTIVE: To summarize evidence on primary Sjögren syndrome drug therapy from randomized controlled trials.
DATA SOURCES: We searched MEDLINE and EMBASE for articles on drug therapy for primary Sjögren syndrome published between January 1, 1986, and April 30, 2010.
STUDY SELECTION: Controlled trials of topical and systemic drugs including adult patients with primary Sjögren syndrome were selected as the primary information source.
RESULTS: The search strategy yielded 37 trials. A placebo-controlled trial found significant improvement in the Schirmer and corneal staining scores, blurred vision, and artificial tear use in patients treated with topical ocular 0.05% cyclosporine. Three placebo-controlled trials found that pilocarpine was associated with improvements in dry mouth (61%-70% vs 24%-31% in the placebo group) and dry eye (42%-53% vs 26%). Two placebo-controlled trials found that cevimeline was associated with improvement in dry mouth (66%-76% vs 35%-37% in the placebo group) and dry eye (39%-72% vs 24%-30%). Small trials (<20 patients) found no significant improvement in sicca outcomes for oral prednisone or hydroxychloroquine and limited benefits for immunosuppressive agents (azathioprine and cyclosporine). A large trial found limited benefits for oral interferon alfa-2a. Two placebo-controlled trials of infliximab and etanercept did not achieve the primary outcome (a composite visual analog scale measuring joint pain, fatigue, and dryness); neither did 2 small trials (<30 patients) testing rituximab, although significant results were observed in some secondary outcomes and improvement compared with baseline.
CONCLUSIONS: In primary Sjögren syndrome, evidence from controlled trials suggests benefits for pilocarpine and cevimeline for sicca features and topical cyclosporine for moderate or severe dry eye. Anti-tumor necrosis factor agents have not shown clinical efficacy, and larger controlled trials are needed to establish the efficacy of rituximab.

PMID 20664046
Khaled Mansour, Carolien J Leonhardt, Wouter W Kalk, Hendrika Bootsma, Klaas J Bruin, Lieuwe J Blanksma, Sjögren Workgroup
Lacrimal punctum occlusion in the treatment of severe keratoconjunctivitis Sicca caused by Sjögren syndrome: a uniocular evaluation.
Cornea. 2007 Feb;26(2):147-50. doi: 10.1097/01.ico.0000244877.30997.6a.
Abstract/Text PURPOSE: A controlled uniocular study to evaluate the short-term efficacy of lacrimal punctum occlusion in the treatment of severe dry eye caused by Sjögren syndrome.
METHODS: Uniocular punctum occlusion by punctum plug in the upper and lower puncta in 1 eye was performed in 20 patients with severe keratoconjunctivitis Sicca caused by Sjögren syndrome. To overcome possible interindividual variability between patients, the other eye, in the same patient, was not occluded and served as a control eye. The eye to be occluded was randomly selected. The patients were instructed to continue using their dry eye medications. Tear function tests (Schirmer test, rose Bengal test, and debris in de cul-de-sac) were performed in both eyes. Subjective complaints (discomfort) were registered for both eyes. All the above-mentioned data were collected before starting the treatment and at least 6 weeks later. The above-mentioned parameters were compared and statistically analyzed in both eyes.
RESULTS: Of the 20 patients, 7 patients dropped out. The remaining 13 patients completed the final analysis. In the occluded eye, we found a significant improvement in both the subjective complaints and the rose Bengal score, but the Schirmer test and the tear mucus score did not change.
CONCLUSION: Punctum occlusion therapy in a short-term study improved the rose Bengal score and discomfort score in our patients and thus may be helpful in the treatment of severe dry eye caused by Sjögren syndrome.

PMID 17251802
P Marsh, S C Pflugfelder
Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjögren syndrome.
Ophthalmology. 1999 Apr;106(4):811-6. doi: 10.1016/S0161-6420(99)90171-9.
Abstract/Text OBJECTIVE: To review the efficacy and side effects of topical nonpreserved corticosteroid therapy for treatment of severe keratoconjunctivitis associated with Sjögren syndrome.
DESIGN: Retrospective, noncomparative case series.
PARTICIPANTS: Twenty-one patients with Sjögren syndrome-associated keratoconjunctivitis sicca and annoying ocular irritation.
INTERVENTION: Treatment with topical nonpreserved methylprednisolone sodium succinate.
MAIN OUTCOME MEASURES: Symptom severity, frequency of instillation of artificial tears, corneal fluorescein staining scores, resolution of filamentary keratitis, steroid-related side effects.
RESULTS: Before starting methylprednisolone therapy, all patients were experiencing moderate-to-severe eye irritation despite prior punctal occlusion in most cases and frequent use of nonpreserved artificial tears by all. After 2 weeks of topical application, three to four times per day, moderate (43%) or complete (57%) relief of irritation symptoms was experienced by all patients and no complications were observed. An average decrease in corneal fluorescein scores of 2.6 +/- 0.5 points (on a 12-point scale) was observed, and filamentary keratitis resolved in all ten eyes with this condition. Therapy was stopped after 2 weeks in eight patients, and six of these patients reported that their symptoms remained at a tolerable level for weeks to months. Lower dose steroid therapy was continued in the remaining patients, whose symptoms worsened after attempted weaning. Complications of corticosteroid therapy in patients receiving prolonged therapy included increased intraocular pressure in one patient at 3 months, worsening of pre-existing posterior subcapsular cataracts in one patient at 6 months, and formation of posterior subcapsular cataracts in another patient at 6 months.
CONCLUSIONS: These findings indicate that topical nonpreserved methylprednisolone is an effective treatment option for patients suffering from severe keratoconjunctivitis sicca who continue to experience bothersome eye irritation despite maximum aqueous enhancement therapies. They also suggest that inflammation is a key pathogenic factor in this condition. Careful monitoring is essential in dry eye patients treated with corticosteroids for more than 2 weeks because steroid-related complications (increased intraocular pressure and cataract formation) were observed after several months of therapy in this series. Because of the chronic nature of this disease and the likelihood of patients developing steroid-related complications with their long-term use, topical nonpreserved methylprednisolone therapy appears to be most appropriate for short-term "pulse" treatment of exacerbations of keratoconjunctivitis sicca.

PMID 10201607
Stephen C Pflugfelder, Steven L Maskin, Bruce Anderson, James Chodosh, Edward J Holland, Cintia S De Paiva, Stephen P Bartels, Teresa Micuda, Howard M Proskin, Roger Vogel
A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance.
Am J Ophthalmol. 2004 Sep;138(3):444-57. doi: 10.1016/j.ajo.2004.04.052.
Abstract/Text PURPOSE: To evaluate loteprednol etabonate ophthalmic 0.5% suspension, versus placebo for treatment of the inflammatory component of keratoconjunctivitis sicca in patients with delayed tear clearance.
DESIGN: Randomized, double-masked, placebo-controlled clinical trial.
METHODS: Sixty-four patients with keratoconjunctivitis sicca and delayed tear clearance were randomly assigned to receive either loteprednol or vehicle 4 times a day for 4 weeks. Patients were evaluated at weeks 2 and 4 of treatment and 2 weeks after treatment was discontinued. Symptoms were scored using a visual analog scale (VAS) of 1 to 100. Corneal fluorescein staining was scored 0 to 4 in five areas. Conjunctival injection was graded 0 to 3 in the inferior bulbar, nasal bulbar, and inferior tarsal areas. Lid margin injection was graded 0 to 3. Safety was assessed by funduscopy, lens examination, biomicroscopy, visual acuity, and Goldmann tonometry, and by monitoring adverse events and changes in symptoms.
RESULTS: In subsets of patients with at least moderate clinical inflammation, there was a significant difference between the loteprednol-treated group and vehicle-treated group after 2 weeks of therapy. The differences did not reach statistical significance at 4 weeks, although the loteprednol-treated patients retained their improvement compared with the vehicle-treated group. Safety evaluations showed both treatments to be well tolerated and similar in the frequency and type of adverse event reported.
CONCLUSION: The use of topical loteprednol etabonate 0.5% 4 times a day may be beneficial in patients who have keratoconjunctivitis sicca with at least a moderate inflammatory component.

PMID 15364229
F B Vivino, I Al-Hashimi, Z Khan, F G LeVeque, P L Salisbury, T K Tran-Johnson, C C Muscoplat, M Trivedi, B Goldlust, S C Gallagher
Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with Sjögren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. P92-01 Study Group.
Arch Intern Med. 1999 Jan 25;159(2):174-81.
Abstract/Text BACKGROUND: Patients with Sjögren syndrome (SS) experience slowly progressive infiltration of lacrimal and salivary glands by mononuclear cells. This leads to diminished secretions, with resultant symptoms of xerostomia and xerophthalmia. Although pilocarpine hydrochloride tablets are currently indicated for the treatment of radiation-induced xerostomia, their effects on dry mouth or dry eyes in patients with SS are unclear.
OBJECTIVE: To assess the safety and efficacy of pilocarpine (Salagen) tablets as symptomatic treatment for dry mouth and dry eyes caused by SS in a multicenter, doubleblind, placebo-controlled trial.
METHODS: After providing written informed consent, 373 patients with primary or secondary SS and clinically significant dry mouth and dry eyes were randomized to receive 2.5-mg pilocarpine, 5-mg pilocarpine, or placebo tablets 4 times daily for 12 weeks. Symptoms were assessed by questionnaires with visual analog scales or categorical checkboxes. Whole-mouth salivary flow rates were measured.
RESULTS: A significantly greater proportion of patients in the 5-mg pilocarpine group showed improvement compared with the placebo group (P< or =.01) in global assessments of dry mouth, dry eyes, and other symptoms of dryness (P< or =.05). Salivary flow was significantly increased 2- to 3-fold (P<.001) after administration of the first dose and was maintained throughout the 12-week study. The most common adverse effect was sweating, and no serious drug-related adverse experiences were reported.
CONCLUSION: Administration of 5-mg pilocarpine tablets 4 times daily (20 mg/d) was well tolerated and produced significant improvement in symptoms of dry mouth and dry eyes and other xeroses in patients with SS.

PMID 9927101
Athena S Papas, Yvonne S Sherrer, Michael Charney, Harvey E Golden, Thomas A Medsger, Bridget T Walsh, Madhu Trivedi, Barry Goldlust, Susan C Gallagher
Successful Treatment of Dry Mouth and Dry Eye Symptoms in Sjögren's Syndrome Patients With Oral Pilocarpine: A Randomized, Placebo-Controlled, Dose-Adjustment Study.
J Clin Rheumatol. 2004 Aug;10(4):169-77. doi: 10.1097/01.rhu.0000135553.08057.21.
Abstract/Text BACKGROUND: : Sjögren's syndrome is characterized by the presence of xerostomia and/or xerophthalmia. Pilocarpine, a muscarinic cholinergic agonist, has been proven to be efficacious in treating radiation-induced xerostomia (up to 30 mg/day) and symptoms of dry mouth in Sjögren's patients (up to 20 mg/day).
OBJECTIVE: : To compare the safety and efficacy of oral pilocarpine (dose-adjusted) versus placebo in the treatment of dry eye and dry mouth symptoms in Sjögren's syndrome at 6 and 12 weeks.
METHODS: : In this 11-center, 256-patient placebo-controlled study, the safety and efficacy of oral pilocarpine (20 mg to 30 mg daily) for relief of Sjögren's-related dry mouth and dry eye symptoms was assessed. Changes in symptoms and salivary flow were measured over 12 weeks.
RESULTS: : Compared with placebo, salivary flow was significantly increased in the pilocarpine group (PCONCLUSIONS: : Significant relief in dry mouth symptoms was noted at 20 mg/day, and significant relief in ocular symptoms, including lower artificial tear requirement, was noted after the dose was increased to 30 mg/day.

PMID 17043506
Cheng-Han Wu, Song-Chou Hsieh, Kuang-Lun Lee, Ko-Jen Li, Ming-Chi Lu, Chia-Li Yu
Pilocarpine hydrochloride for the treatment of xerostomia in patients with Sjögren's syndrome in Taiwan--a double-blind, placebo-controlled trial.
J Formos Med Assoc. 2006 Oct;105(10):796-803. doi: 10.1016/S0929-6646(09)60266-7.
Abstract/Text BACKGROUND/PURPOSE: Sjögren's syndrome (SS) is characterized by diminished exocrine secretions with the resultant symptoms of dry mouth and dry eye. As genetic predisposition and ethnicity may alter the effectiveness of drug treatment, evaluation of the efficacy and safety of the secretagogue pilocarpine hydrochloride in the treatment of xerostomia in patients with SS in different populations is needed.
METHODS: Forty-four patients with SS were enrolled in this double-blind, placebo-controlled trial. Patients were randomized to receive 5 mg pilocarpine (Salagen) or placebo tablet four times daily for 12 weeks. Global evaluation and subjective responses of patients were assessed by questionnaires with visual analog scales and categorical checkboxes. Saliva production was also measured by modified Saxon's test.
RESULTS: Pilocarpine treatment significantly improved global assessment of dry mouth, symptoms associated with dry mouth (mouth comfort, ability to sleep and ability to speak), and saliva production compared to placebo. The drug was well tolerated and the most common adverse effect was sweating (5/23, 21.7%) resulting from the muscarinic agonist action of the drug. No serious drug-related adverse effect was found in this study.
CONCLUSION: The results of this study suggest that therapy with 5 mg pilocarpine four times daily is effective, safe and well tolerated for the relief of oral symptoms in patients with SS in Taiwan.

PMID 17000452
Dianne Petrone, John J Condemi, Rose Fife, Oscar Gluck, Stanley Cohen, Paul Dalgin
A double-blind, randomized, placebo-controlled study of cevimeline in Sjögren's syndrome patients with xerostomia and keratoconjunctivitis sicca.
Arthritis Rheum. 2002 Mar;46(3):748-54. doi: 10.1002/art.510.
Abstract/Text OBJECTIVE: To evaluate the safety and efficacy of 2 dosages of cevimeline for the treatment of xerostomia and keratoconjunctivitis sicca in patients with Sjögren's syndrome.
METHODS: A 12-week double-blind, randomized, placebo-controlled study was performed. Patients were randomly assigned to receive either placebo, 15 mg of cevimeline 3 times daily, or 30 mg of cevimeline 3 times daily. Patients were evaluated at baseline and throughout the study for their global assessment of dryness (mouth, eyes, overall) as well as their subjective assessment of the specific symptoms of dry mouth and dry eyes. Total saliva and tear flow also were measured.
RESULTS: Patients taking 30 mg of cevimeline 3 times daily had statistically significant improvements in their subjective global assessment of dry eyes (P = 0.0453), dry mouth (P = 0.0004), and increased salivary flow (P = 0.007). Patients receiving the 30-mg dosage also showed greater objective improvement (increased salivary and lacrimal flow rates, as measured by Schirmer's test) than did patients receiving placebo. Frequently reported adverse events included headache, increased sweating, abdominal pain, and nausea.
CONCLUSION: Treatment with cevimeline at a dosage of 30 mg 3 times daily resulted in substantive improvement by increasing the rate of saliva and tear flow in patients with Sjögren's syndrome, as well as improving subjective symptoms of dry mouth, dry eyes, and overall dryness. The 15-mg dosage relieved some symptoms, and both dosages were well tolerated.

PMID 11920411
Rose S Fife, Walter F Chase, Robin K Dore, Craig W Wiesenhutter, Peter B Lockhart, Elizabeth Tindall, James Y Suen
Cevimeline for the treatment of xerostomia in patients with Sjögren syndrome: a randomized trial.
Arch Intern Med. 2002 Jun 10;162(11):1293-300.
Abstract/Text BACKGROUND: Cevimeline hydrochloride is a cholinergic agent with muscarinic agonist activity prominently affecting the M1 and M3 receptors prevalent in exocrine glands. We evaluated the safety and efficacy of cevimeline in the treatment of xerostomia in patients with Sjögren syndrome.
METHODS: Seventy-five patients with Sjögren syndrome and associated salivary gland dysfunction were enrolled in a double-blind, randomized, placebo-controlled trial at 8 university- and office-based outpatient clinical facilities in the United States. Eligible study participants were randomized to receive 30 mg of cevimeline 3 times daily, 60 mg of cevimeline 3 times daily, or placebo for 6 weeks. Subjective responses were determined using global patient evaluation and visual analog scales. Salivary flow was measured objectively.
RESULTS: Sixty-one participants completed the study. Patients in both cevimeline groups had significant improvements in dry mouth, as indicated by symptoms, salivary flow, and use of artificial saliva, compared with the placebo group. The drug was generally well tolerated, with expected adverse events resulting from the drug's muscarinic agonist action. Fourteen patients withdrew from the study because of adverse events, the most frequent being nausea.
CONCLUSIONS: Therapy with cevimeline, 30 mg 3 times daily, seems to be well tolerated and to provide substantive relief of xerostomia symptoms. Although both dosages of cevimeline provided symptomatic improvement, 60 mg 3 times daily was associated with an increase in the occurrence of adverse events, particularly gastrointestinal tract disorders. Use of 30 mg of cevimeline provides a new option for the treatment of xerostomia in Sjögren syndrome.

PMID 12038948
P P Chakraborty, R Bhattacharjee, A K Maiti, S K Mandal
Recurrent submandibular gland swelling as the initial presentation of Sjogren's syndrome.
J Assoc Physicians India. 2007 Jan;55:44.
Abstract/Text
PMID 17444343
Toshiro Sugimoto, Takashi Uzu, Atsunori Kashiwagi
Recurrent parotitis as a first manifestation of adult primary Sjögren's syndrome.
Intern Med. 2006;45(13):831-2. doi: 10.2169/internalmedicine.45.1730. Epub 2006 Aug 1.
Abstract/Text
PMID 16880710
H Alp, Z Orbak, T Erdogan, K Karabag, N Gursan
Recurrent parotitis as a first manifestation in a child with primary Sjogren's syndrome.
West Indian Med J. 2011 Dec;60(6):685-7.
Abstract/Text Recurrent parotitis is an acute, severe inflammation of one or both parotid glands, the major salivary glands in young children. We report the case of a seven-year old boy with Primary Sjogrens syndrome (PSS) who presented with 15 episodes of painful recurrent bilateral swellings of the parotid glands over a four-year period.

PMID 22512231
Kevin Baszis, Dana Toib, Megan Cooper, Anthony French, Andrew White
Recurrent parotitis as a presentation of primary pediatric Sjögren syndrome.
Pediatrics. 2012 Jan;129(1):e179-82. doi: 10.1542/peds.2011-0716. Epub 2011 Dec 19.
Abstract/Text Parotitis is a common condition seen in the pediatric population, usually as an isolated occurrence associated with viral or bacterial infection. The differential diagnosis expands when recurrent parotitis is encountered. One etiology is primary pediatric Sjögren syndrome (SS), an autoimmune condition typically associated with dryness of the eyes and mouth in adults. Pediatric patients often present with isolated recurrent bilateral parotitis, however, and we describe 4 such cases in children aged 9 to 17 years at presentation. Despite lack of ocular complaints, 3 of these patients had ocular findings on ophthalmologic exam. Our patients also exhibited classic laboratory abnormalities, including positive antinuclear antibody, SS A, and SS B antibodies; presence of rheumatoid factor; and hypergammaglobulinemia. Consideration of SS in the child with recurrent parotitis is important for timely and appropriate referral and treatment. We review the differential diagnosis of parotitis in children as well as the salient features of pediatric SS.

PMID 22184654
Mahmut Civilibal, Nur Canpolat, Ayse Yurt, Sebuh Kurugoglu, Sibel Erdamar, Onur Bagci, Lale Sever, Ozgur Kasapcopur, Salim Caliskan, Nil Arisoy
A child with primary Sjögren syndrome and a review of the literature.
Clin Pediatr (Phila). 2007 Oct;46(8):738-42. doi: 10.1177/0009922807301945. Epub 2007 May 16.
Abstract/Text Primary Sjögren syndrome (pSS) is an uncommon disease in childhood. Childhood pSS might have different clinical manifestations than adult pSS. We describe a 13-year-old girl with multiple episodes of bilateral parotid swelling lasting 2 years. Her history included severe arthralgia, local edema, and purpura episodes since 9 years of age. During her 3-week hospitalization, 2 episodes of parotid swelling occurred, which both resolved in 48 hours. Ultrasonography and magnetic resonance images of parotid glands showed parenchymal inhomogeneity related to adipose degeneration and nodular pattern. Investigations showed elevated erythrocyte sedimentation rate, the presence of hypergammaglobulinemia, positive antinuclear antibody, and elevated rheumatoid factor, anti-Sjögren syndrome antigen A, and anti-Sjögren syndrome antigen B. Histopathologic examination of labial minor salivary glands revealed focal periductal lymphocytic infiltrate and sialoduct ectasia. She was diagnosed as having pSS. Recurrent parotid swelling is a more characteristic feature of disease in children, and this finding should alert the clinician to the possible diagnosis of pSS.

PMID 17507575
Shinsuke Yasuda, Nobutaka Ogura, Tetsuya Horita, Izumi Yasuda, Takaya Hioka, Nobuo Kondo, Atsushi Fujisaku
Abacterial prostatitis and primary biliary cirrhosis with SjOgren's syndrome.
Mod Rheumatol. 2004;14(1):70-2. doi: 10.1007/s10165-003-0269-y.
Abstract/Text In patients with SjOgren's syndrome (SS), the salivary and lacrimal glands are often affected, although other epithelial tissues can become inflamed. Here, we report the first case of abacterial prostatitis in a patient with SS complicated by primary biliary cirrhosis. Histologically, the distribution and subpopulation of infiltrating lymphocytes were similar in the salivary gland, liver, and prostate. Treatment with steroid was successful. We speculate that the prostate may be one of the target organs in SS.

PMID 17028809
P C Fox, M Datiles, J C Atkinson, A A Macynski, J Scott, D Fletcher, I H Valdez, R H Kurrasch, R Delapenha, W Jackson
Prednisone and piroxicam for treatment of primary Sjögren's syndrome.
Clin Exp Rheumatol. 1993 Mar-Apr;11(2):149-56.
Abstract/Text Primary Sjögren's syndrome is a systemic autoimmune exocrinopathy characterized by a lymphoplasmacytic infiltrate and destruction of salivary and lacrimal glandular tissues. There is no widely accepted or effective systemic therapy for this disorder. The purpose of this 6-month randomized, double-blinded, placebo-controlled study was to examine the effects of prednisone (30 mg, alternate days), piroxicam (20 mg, daily), or placebo on the salivary, lacrimal and immunologic alterations of primary Sjögren's syndrome. Eight patients were enrolled in each group. Salivary and lacrimal function were assessed at entry and at the completion of treatment. Labial minor salivary gland tissue was obtained at these times and examined for intensity of infiltration (focus scores) and for the relative proportion of glandular elements. Serologic and subjective evaluations were done as well, and patients were monitored for therapy-related side effects. Neither active treatment led to significant improvement in salivary or lacrimal function, although prednisone improved salivary flow in selected patients and was associated with positive subjective responses. Prednisone also significantly decreased the serum total protein, IgG, IgA, and sedimentation rate and increased the white cell count. There were no significant alterations in either focus scores or the percentage of glandular component tissues of minor glands with either active treatment. This study demonstrated that 6 months of prednisone or piroxicam at the doses utilized failed to improve the histological or functional parameters of salivary and lacrimal glands in primary Sjögren's syndrome.

PMID 8508556
Shingo Nakayamada, Takashi Fujimoto, Akitaka Nonomura, Kazuyoshi Saito, Shinobu Nakamura, Yoshiya Tanaka
Usefulness of initial histological features for stratifying Sjogren's syndrome responders to mizoribine therapy.
Rheumatology (Oxford). 2009 Oct;48(10):1279-82. doi: 10.1093/rheumatology/kep228. Epub 2009 Aug 11.
Abstract/Text OBJECTIVES: To evaluate the response of patients with SS to mizoribine therapy in relation to histological features of minor salivary glands.
METHODS: Forty patients definitely diagnosed as having SS were treated with mizoribine (150 mg/day). Thirty-four untreated patients matched for age, baseline salivary secretion, etc., served as controls. Salivary secretion volume (measured by the Saxon test) and serum IgG level were measured before and after 24 weeks of treatment. Each histological finding (lymphocytic infiltration, acinar atrophy and intralobular fibrosis) was graded at baseline and the therapeutic responses were compared with the grade at 24 weeks in both the groups.
RESULTS: There was a significant increase of the salivary secretion volume after treatment with mizoribine as compared with the untreated control group. The effect of mizoribine on salivary secretion was more marked in patients having moderate lymphocytic infiltration and moderate or less severe acinar atrophy and intralobular fibrosis at baseline.
CONCLUSIONS: Mizoribine was clinically effective in patients with SS whose minor salivary glands had moderate cell infiltration and were free of intralobular fibrosis. The drug was less effective in patients who presented intralobular fibrosis. Histological evaluation of the minor salivary glands may serve to predict the response of SS patients to mizoribine therapy.

PMID 19671696
Shingo Nakayamada, Kazuyoshi Saito, Hisanori Umehara, Noriyoshi Ogawa, Takayuki Sumida, Satoshi Ito, Seiji Minota, Hiroyuki Nara, Hirobumi Kondo, Jun Okada, Tsuneyo Mimori, Hajime Yoshifuji, Hajime Sano, Naoaki Hashimoto, Susumu Sugai, Yoshiya Tanaka
Efficacy and safety of mizoribine for the treatment of Sjögren's syndrome: a multicenter open-label clinical trial.
Mod Rheumatol. 2007;17(6):464-9. doi: 10.1007/s10165-007-0627-2. Epub 2007 Dec 20.
Abstract/Text This multicenter clinical trial was performed to evaluate the efficacy and safety of mizoribine for the treatment of Sjögren's syndrome. Fifty-nine patients with a definite diagnosis of Sjögren's syndrome received 150;Smg of mizoribine daily for 16 weeks. The salivary secretion volume was determined at baseline, at weeks 8 and 16 after the start of the study treatment by the Saxon test, and clinical manifestations were assessed by the investigator and the patients using a 10-cm visual analog scale (VAS). Adverse drug reactions were reported in 18 patients, of whom 6 patients had to discontinue the study due to such adverse reactions; however, no serious adverse drug reactions definitely related to the study drug were noted. The salivary secretion volume, the rate of change in salivary secretion, the patients' own assessments of dry mouth and dry eyes, the investigators' assessment of oral sicca symptoms, and the investigators' overall assessment improved following the treatment regimen with statistical significance at week 16 after the start of treatment in comparison to the baseline values. These results suggested that mizoribine may be effective in producing a subjective and objective amelioration of the glandular symptoms in patients with Sjögren's syndrome, without observing any serious adverse effects related to this drug.

PMID 18084697
F N Skopouli, P Jagiello, N Tsifetaki, H M Moutsopoulos
Methotrexate in primary Sjögren's syndrome.
Clin Exp Rheumatol. 1996 Sep-Oct;14(5):555-8.
Abstract/Text OBJECTIVE: To determine the safety and efficacy of methotrexate (MTX) in the treatment of primary Sjögren's syndrome (SS).
METHODS: An open, one-year pilot study of MTX (0.2 mg/kg body weight taken weekly) for the treatment of SS was performed. Seventeen patients with primary SS according to EEC criteria were enrolled in the study. Outcome was determined on the basis of clinical and laboratory parameters.
RESULTS: Weekly administration of MTX resulted in improvement of the main subjective symptoms (dry mouth and eyes) as well as in the frequency of parotid gland enlargement, dry cough and purpura. However, no improvement in the objective parameters of dry eyes and dry mouth were observed. Persistent asymptomatic elevation of the hepatic transaminase levels led to a dosage reduction in 7 patients (41%).
CONCLUSIONS: Weekly MTX may be an acceptable form of therapy for SS patients. Double-blind trials are needed to substantiate the efficacy of this therapeutic modality.

PMID 8913659
J M Meijer, P M Meiners, A Vissink, F K L Spijkervet, W Abdulahad, N Kamminga, E Brouwer, C G M Kallenberg, H Bootsma
Effectiveness of rituximab treatment in primary Sjögren's syndrome: a randomized, double-blind, placebo-controlled trial.
Arthritis Rheum. 2010 Apr;62(4):960-8. doi: 10.1002/art.27314.
Abstract/Text OBJECTIVE: To study the efficacy and safety of B cell depletion with rituximab, a chimeric murine/human anti-CD20 monoclonal antibody, in patients with primary Sjögren's syndrome (SS) in a double-blind, randomized, placebo-controlled trial.
METHODS: Patients with active primary SS, as determined by the revised American-European Consensus Group criteria, and a rate of stimulated whole saliva secretion of > or =0.15 ml/minute were treated with either rituximab (1,000 mg) or placebo infusions on days 1 and 15. Patients were assigned randomly to a treatment group in a ratio of 2:1 (rituximab:placebo). Followup was conducted at 5, 12, 24, 36, and 48 weeks. The primary end point was the stimulated whole saliva flow rate, while secondary end points included functional, laboratory, and subjective variables.
RESULTS: Thirty patients with primary SS (29 female) were randomly allocated to a treatment group. The mean +/- SD age of the patients receiving rituximab was 43 +/- 11 years and the disease duration was 63 +/- 50 months, while patients in the placebo group were age 43 +/- 17 years and had a disease duration of 67 +/- 63 months. In the rituximab group, significant improvements, in terms of the mean change from baseline compared with that in the placebo group, were found for the primary end point of the stimulated whole saliva flow rate (P = 0.038 versus placebo) and also for various laboratory parameters (B cell and rheumatoid factor [RF] levels), subjective parameters (Multidimensional Fatigue Inventory [MFI] scores and visual analog scale [VAS] scores for sicca symptoms), and extraglandular manifestations. Moreover, in comparison with baseline values, rituximab treatment significantly improved the stimulated whole saliva flow rate (P = 0.004) and several other variables (e.g., B cell and RF levels, unstimulated whole saliva flow rate, lacrimal gland function on the lissamine green test, MFI scores, Short Form 36 health survey scores, and VAS scores for sicca symptoms). One patient in the rituximab group developed mild serum sickness-like disease.
CONCLUSION: These results indicate that rituximab is an effective and safe treatment strategy for patients with primary SS.

PMID 20131246
Hiroto Tsuboi, Isao Matsumoto, Shinya Hagiwara, Tomoya Hirota, Hiroyuki Takahashi, Hiroshi Ebe, Masahiro Yokosawa, Chihiro Hagiya, Hiromitsu Asashima, Chinatsu Takai, Haruka Miki, Naoto Umeda, Yuya Kondo, Hiroshi Ogishima, Takeshi Suzuki, Shintaro Hirata, Kazuyoshi Saito, Yoshiya Tanaka, Yoshiro Horai, Hideki Nakamura, Atsushi Kawakami, Takayuki Sumida
Efficacy and safety of abatacept for patients with Sjögren's syndrome associated with rheumatoid arthritis: rheumatoid arthritis with orencia trial toward Sjögren's syndrome Endocrinopathy (ROSE) trial-an open-label, one-year, prospective study-Interim analysis of 32 patients for 24 weeks.
Mod Rheumatol. 2015 Mar;25(2):187-93. doi: 10.3109/14397595.2014.951144. Epub 2014 Sep 11.
Abstract/Text Abstract Objective. To assess the efficacy and safety of abatacept for secondary Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). Methods. The primary endpoint of this 1-year, open-labeled, prospective, observational multicenter study of RA-associated secondary SS was the rate of SDAI remission at 52 weeks after initiation of abatacept therapy. The secondary endpoints included that of Saxson's test and Schirmer's test. Adverse events during the study period were also analyzed. Results. Thirty-two patients (all females) were enrolled in this study. Interim analysis at 24 weeks included assessment of efficacy (n = 31) and safety (n = 32). The mean SDAI decreased from 19.8 ± 11.0 (± SD) at baseline to 9.9 ± 9.9 at 24 weeks (P < 0.05). Patients with clinical remission, as assessed by SDAI, increased from 0 patient (0 week) to 8 patients (25.8%) at 24 weeks. Saliva volume (assessed by Saxson's test) increased slightly from 2232 ± 1908 (0 week) to 2424 ± 2004 (24 weeks) mg/2 min (n = 29). In 11 patients with Greenspan grading 1/2 of labial salivary glands biopsy, saliva volume increased from 2945 ± 2090 (0 week) to 3419 ± 2121 (24 weeks) mg/2 min (P < 0.05). Schirmer's test for tear volume showed increase from 3.6 ± 4.6 (0 week) to 5.5 ± 7.1 (24 weeks) mm/5 min (n = 25; P < 0.05). Five adverse events occurred in five of 32 patients (15.6%), and three of these events were infections. Conclusion. Abatacept seems to be effective for both RA and RA-related secondary SS.

PMID 25211401
Ju-Hong Shi, Hong-Rui Liu, Wen-Bing Xu, Rui-E Feng, Zhu-Hua Zhang, Xin-Lun Tian, Yuan-Jue Zhu
Pulmonary manifestations of Sjögren's syndrome.
Respiration. 2009;78(4):377-86. doi: 10.1159/000214841. Epub 2009 Apr 22.
Abstract/Text BACKGROUND: Primary Sjögren's syndrome (PSS) is associated with various histological patterns of interstitial lung disease. Although chest images and lung function studies showed that lung involvement predominantly occurs in small airways, pathological findings were not consistent with the results of high-resolution CT (HRCT) and lung function tests.
OBJECTIVES: To investigate the pathological characteristics of PSS-associated interstitial lung disease (PSS-ILD) and their relationship with HRCT lung function tests.
METHODS: Fourteen patients diagnosed as PSS who underwent surgical lung biopsy in Peking Union Medical College Hospital from October 2000 to October 2006 were reviewed. Histopathologic findings, radiologic findings and lung function tests were analyzed.
RESULTS: The study included 13 women. The median age was 46 years. Most patients presented with dyspnea and cough. CT scans revealed bilateral ground-glass, consolidative, reticular and nodular opacities and cyst lesions. The histological patterns included nonspecific interstitial pneumonia (NSIP) cellular pattern associated with organizing pneumonia (OP), NSIP mixed pattern associated with OP, noncaseating granulomas, chronic bronchiolitis, follicular bronchiolitis, constrictive bronchiolitis, lymphocytic interstitial pneumonia associated with follicular bronchiolitis, NSIP mixed pattern associated with follicular bronchiolitis, NSIP mixed pattern coexisting with chronic bronchiolitis, OP associated with chronic bronchiolitis, and noncaseating granulomas coexisting with OP. Treatment included prednisone and cyclophosphamide. During the follow-up period (median 38 months), most patients improved or remained stable. The patient with constrictive bronchiolitis died from progression of primary disease.
CONCLUSIONS: The histopathologic patterns of PSS-ILD included lung interstitial involvement and small airway involvement or both. Corticosteroid therapy combined with cyclophosphamide was administered with a favorable response in the majority of patients.

Copyright © 2009 S. Karger AG, Basel.
PMID 19390161
Saugar Maripuri, Joseph P Grande, Thomas G Osborn, Fernando C Fervenza, Eric L Matteson, James V Donadio, Marie C Hogan
Renal involvement in primary Sjögren's syndrome: a clinicopathologic study.
Clin J Am Soc Nephrol. 2009 Sep;4(9):1423-31. doi: 10.2215/CJN.00980209. Epub 2009 Aug 13.
Abstract/Text BACKGROUND & OBJECTIVES: Renal pathology and clinical outcomes in patients with primary Sjögren's syndrome (pSS) who underwent kidney biopsy (KB) because of renal impairment are reported.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-four of 7276 patients with pSS underwent KB over 40 years. Patient cases were reviewed by a renal pathologist, nephrologist, and rheumatologist. Presentation, laboratory findings, renal pathology, initial treatment, and therapeutic response were noted.
RESULTS: Seventeen patients (17 of 24; 71%) had acute or chronic tubulointerstitial nephritis (TIN) as the primary lesion, with chronic TIN (11 of 17; 65%) the most common presentation. Two had cryoglobulinemic GN. Two had focal segmental glomerulosclerosis. Twenty patients (83%) were initially treated with corticosteroids. In addition, three received rituximab during follow-up. Sixteen were followed after biopsy for more than 12 mo (median 76 mo; range 17 to 192), and 14 of 16 maintained or improved renal function through follow-up. Of the seven patients presenting in stage IV chronic kidney disease, none progressed to stage V with treatment.
CONCLUSIONS: This case series supports chronic TIN as the predominant KB finding in patients with renal involvement from pSS and illustrates diverse glomerular lesions. KB should be considered in the clinical evaluation of kidney dysfunction in pSS. Treatment with glucocorticoids or other immunosuppressive agents appears to slow progression of renal disease. Screening for renal involvement in pSS should include urinalysis, serum creatinine, and KB where indicated. KB with characteristic findings (TIN) should be considered as an additional supportive criterion to the classification criteria for pSS because it may affect management and renal outcome.

PMID 19679669
Ichiro Katayama, Yorihisa Kotobuki, Eiji Kiyohara, Hiroyuki Murota
Annular erythema associated with Sjögren's syndrome: review of the literature on the management and clinical analysis of skin lesions.
Mod Rheumatol. 2010 Apr;20(2):123-9. doi: 10.1007/s10165-009-0257-y. Epub 2010 Jan 8.
Abstract/Text Annular erythema has been recognized to be a specific, cutaneous manifestation associated with Sjögren's syndrome. Based on a search of the literature up to 2007, annular erythema with Sjögren's syndrome (AESS) preferentially occurs in Asian but not in Western populations. However, the precise clinical course and standard regimen for the management of AESS have remained obscure, primarily because of its rare occurrence in Western populations and the fact that most Asian cases are isolated reports. In this study, 28 cases of AESS from our department and 92 cases distilled from the literature were enrolled in a retrospective study to evaluate the clinical characteristics and most desirable management of this skin manifestation in Sjögren's syndrome. We found that 75% of all cases with AESS were positive for both anti-SSA and anti-SSB antibodies. Multiple therapeutic options are available to treat AESS, including oral steroids. Several anti-malaria drugs or tacrolimus ointment have also been reported to be effective against AESS. AESS is a distinct clinical entity, and a small dose of prednisolone (approx. 10 mg) is sufficient to control diseases activity, except in some cases with systemic manifestations, and this treatment has a more rapid clinical effect than topical steroids.

PMID 20054701

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