Kazuko Kitagawa

American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort.

We propose new classification criteria for Sjögrens syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS.

Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders

Background: Mikulicz’s disease (MD) has been considered as one manifestation of Sjögren’s syndrome (SS). Recently, it has also been considered as an IgG4-related disorder. Objective: To determine the differences between IgG4-related disorders including MD and SS. Methods: A study was undertaken to investigate patients with MD and IgG4-related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG4-positive multiorgan lymphoproliferative syndrome (IgG4+MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG4 (>135 mg/dl) and infiltration of IgG4+ plasma cells in the tissue (IgG4+/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG4+MOLPS and 31 patients with typical SS were compared. Results: The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG4+MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG2, IgG4 and IgE levels were significantly increased in IgG4+MOLPS. Histological specimens from patients with IgG4+MOLPS revealed marked IgG4+ plasma cell infiltration. Many patients with IgG4+MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG4+ cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG4+MOLPS treated with glucocorticoids showed marked clinical improvement. Conclusion: Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG4+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG4+MOLPS.

Prevalence of dry eye in Japanese eye centers

Abstract• Background: The purpose of the investigation was to ascertain the prevalence of dry eye in new outpatients. • Methods: A total of 2127 consecutive new outpatients seen in eight Japanese centers from April 1992 to January 1993 underwent comprehensive examinations, including double vital staining and measurement of tear film break-up time, basal tear secretion, and tear clearance. Dry eye was diagnosed if patients had abnormalities of both the tear film and the ocular surface. • Results: Three hundred fifty-nine patients (17%) had dry eye. There was no seasonal pattern for dry eye. The condition was significantly more common in Tokyo than in suburban areas (P < 0.01). The prevalence of dry eye in visual display terminal (VDT) users and contact lens (CL) wearers was significantly higher than in non-VDT users and non-CL wearers (P < 0.05 and P < 0.02, respectively). • Conclusion: Our findings suggest that dry eye is one of the most common ocular disorders encountered by physicians. Furthermore, if patients use VDTs or wear CLs, the likelihood of dry eye occurring is higher.

A simplified quantitative method for assessing keratoconjunctivitis sicca from the Sjögren's Syndrome International Registry.

PURPOSE To describe, apply, and test a new ocular grading system for assessing keratoconjunctivitis sicca (KCS) using lissamine green and fluorescein. DESIGN Prospective, observational, multicenter cohort study. METHODS The National Institutes of Health-funded Sjögrens Syndrome International Registry (called Sjögrens International Collaborative Clinical Alliance [SICCA]) is developing standardized classification criteria for Sjögren syndrome (SS) and is creating a biospecimen bank for future research. Eight SICCA ophthalmologists developed a new quantitative ocular grading system (SICCA ocular staining score [OSS]), and we analyzed OSS distribution among the SICCA cohort and its association with other phenotypic characteristics of SS. The SICCA cohort includes participants ranging from possibly early SS to advanced disease. Procedures include sequenced unanesthetized Schirmer test, tear break-up time, ocular surface staining, and external eye examination at the slit lamp. Using statistical analyses and proportional Venn diagrams, we examined interrelationships between abnormal OSS (>or=3) and other characteristics of SS (labial salivary gland [LSG] biopsy with focal lymphocytic sialadenitis and focus score >1 positive anti-SS A antibodies, anti-SS B antibodies, or both). RESULTS Among 1208 participants, we found strong associations between abnormal OSS, positive serologic results, and positive LSG focus scores (P < .0001). Analysis of the overlapping relationships of these 3 measures defined a large group of participants who had KCS without other components of SS, representing a clinical entity distinct from the KCS associated with SS. CONCLUSIONS This new method for assessing KCS will become the means for diagnosing the ocular component of SS in future classification criteria. We find 2 forms of KCS whose causes may differ.

Efficacy and retention rate of two types of silicone punctal plugs in patients with and without Sjögren syndrome.

Objective: To compare the efficacy, retention rates, and complications of two types of silicone lacrimal punctal plugs in patients with or without Sjögren syndrome. Methods: We studied 36 patients with keratoconjunctivitis sicca (KCS) including 17 cases with Sjögren syndrome (SS) and 19 without SS. The fluorescein and rose bengal staining scores and the Schirmer values with and without nasal stimulation were evaluated before and after insertion of the Eagle Plugs and the punctal plugs (FCI Punctal Plugs). The retention rates and complications of these plugs were also investigated. Results: The staining scores were significantly improved after the insertion of the plugs, but the Schirmer values did not increase significantly in either SS or non-SS patients. A spontaneous loss of the plugs was observed in 29% of all plugs within 1 month after insertion. The Eagle Plugs were lost more frequently, and plugs in the upper punctum were lost more often for the Eagle Plugs. There was one case of granulomatous proliferation and two cases of punctal infection with the FCI Punctal Plugs. Conclusions: Both types of punctal plugs led to an improvement of the fluorescein and rose bengal staining scores in eyes with KCS. The difference in the retention rate and complications between the two types of plugs was probably caused by the differences in the material and the design of the plugs. Close monitoring is necessary to check for loss of plugs and to prevent complications.

Lactoferrin Glu561Asp facilitates secondary amyloidosis in the cornea

Aim: To elucidate the pathogenic mechanism of amyloid formation in corneal amyloidosis with trichiasis. Methods: Ophthalmological examination was performed in nine patients to determine secondary corneal amyloidosis with trichiasis. Congo red staining and immunohistochemistry using anti-human lactoferrin antibody were used for biopsied corneal samples. For genetic analyses, single strand conformation polymorphism (SSCP), direct DNA sequence analysis, and polymerase chain reaction (PCR) induced mutation restriction analysis (IMRA) were employed to detect lactoferrin gene polymorphism. Results: All patients had had trichiasis at least for 1 year, and all amyloid-like deposits were found in one eye with trichiasis. Ophthalmological examination revealed that eight patients showed gelatinous type of amyloid deposition and one showed lattice type of amyloid deposition. Studies of biopsied corneal samples with Congo red stain revealed positive staining just under the corneal epithelial cells. Immunoreactivity of anti-human lactoferrin antibodies was recognised in all tissues with positive Congo red staining. Lactoferrin gene analysis revealed that seven patients were heterozygotic and two were homozygotic for lactoferrin Glu561Asp. The frequency of the polymorphism in the patients was significantly different from that in 56 healthy control subjects. Conclusion: Lactoferrin Glu561Asp is a key polymorphism related to facilitating amyloid formation in corneal amyloidosis with trichiasis.

Clonality analysis of lymphoproliferative disorders in patients with Sjögren's syndrome

The aim of this study was to clarify the nature of the clonal lymphocyte infiltration in Sjögrens syndrome (SS) patients associated with lymphoproliferative disorders. We examined B cell clonality in lymphoproliferative tissues from six primary SS patients associated with lymphoproliferative disorders or lymphoma by cloning and sequencing of the gene rearrangement of the immunoglobulin heavy chain complementarity determining region 3 (IgVH–CDR3). Three patients with sequential observation showed progressional clonal expansion with the presence of the same subclone in different tissues during the course of disease. Among them, one patient developed mucosa‐associated lymphoid tissue (MALT) lymphoma in glandular parotid. The other three SS patients concomitant with malignant B cells lymphomas showed different clonal expansion of B cells between nodal sites and salivary glands. The cloanality analysis indicated that monoclonal B cell population could spread from one glandular site to another site during the course of SS, suggesting that the malignant clone may arise from the general abnormal microenvironment, not restricted to the glandular tissue, in some SS patients.

Early Lens Changes Seen in Patients with Atopic Dermatitis Applying Image Analysis Processing of Scheimpflug and Specular Microscopic Images

In order to know the initial lens changes that accompany atopic dermatitis (AD), 99 patients diagnosed dermatologically to have AD without any or with slight external ocular inflammations and with no habit of rubbing the eyelid due to severe itching were examined opthalmologically. Clinically, none of them showed any cataractous changes in their eyes. For the sake of comparison with the above population, 4 AD patients with cataractous eyes, 49 renal transplantation patients who were administered steroids over a long period of time but clinically had no cataractous lenses, and 94 healthy individuals with transparent lenses were also selected as subjects. The crystalline lenses of the subjects were examined using an anterior eye segment analysis system and specular microscopy. From Scheimpflug slit images of the lens, light scattering intensity of different lens layers was measured as an indicator of lens transparency changes. The subcapsular basement membrane and changes in the lens epithelial layers were analyzed from specular images of these areas by image processing. Results and considerations from the investigations were: (1) Initial lens changes in cases with AD which may be occult cataractous findings were often detectable. (2) Cataract associated with AD can be accelerated by steroid administration or the habit of strongly rubbing the eyelid, but this may not be the original cause of cataract formation. (3) Two types of cataract are seen in patients with AD: (a) anterior subcapsular plaque formation and (b) anterior and posterior subcapsular opacity formation. The latter type, however, is also accompanied by epithelial damage from the early stage. (4) Significant numbers of patients with AD who have not yet shown manifest lens changes were found among the subjects.

Effect of rebamipide ophthalmic suspension on signs and symptoms of keratoconjunctivitis sicca in Sjögren syndrome patients with or without punctal occlusions.

Purpose: The aim of this study was to investigate the efficacy of 2% rebamipide suspension in treatment of keratoconjunctivitis sicca (KCS) in patients with Sjögren syndrome (SS) with or without punctal occlusions. Methods: Thirty patients with SS, diagnosed based on the presence of autoantibodies and/or focus score >1 on lip biopsies, with corneal fluorescein staining scores (FSS) >3, and conjunctival lissamine green–staining scores (LSS) >3, were treated 4 times daily for 4 weeks with 2% rebamipide ocular suspension. Ocular examinations were performed before treatment and 2 and 4 weeks after treatment to evaluate FSS (0–9), LSS (0–6), and tear film break-up time (BUT). Hyaluronate and/or artificial tears were not discontinued. The patients were interviewed regarding the 5 major KCS symptoms, foreign body sensation, dry eye sensation, photophobia, ocular pain, and blurred vision, with each graded from none (0) to very severe (4). Results: Of the 30 patients, 3 failed to attend all sessions, leaving 27 (25 females, 2 males, mean age 62.5 ± 10.8 years) to be studied. FSS and LSS showed improvement at week 2, but BUT showed improvement later, at week 4. All 5 symptoms improved significantly. When the patients were divided into 3 groups according to the presence of punctal occlusions, FSS and LSS were found to improve in all groups, but BUT improved only in patients with both puncta occluded at week 4. Conclusions: Rebamipide ophthalmic suspension was effective in treating KCS of patients with SS, probably by increasing mucins and suppressing inflammatory cytokines. Punctal occlusions resulted in sufficient retention of tear fluid to enhance the activities of rebamipide and improve BUT.

Classification of secondary corneal amyloidosis and involvement of lactoferrin.

PURPOSE To classify secondary corneal amyloidosis (SCA) by its clinical appearance, to analyze the demographics of the patients, and to determine the involvement of lactoferrin. DESIGN Retrospective, observational, noncomparative, multicenter study. PARTICIPANTS Twenty-nine eyes of 29 patients diagnosed with SCA by corneal specialists at 9 ophthalmologic institutions in Japan were studied. METHODS The clinical appearance of SCA was determined by slit-lamp biomicroscopy and was classified into 3 types. The demographics of the patients, for example, age, gender, and the duration of the basic disease (trichiasis, keratoconus, and unknown), were determined for each clinical type. Surgically excised tissues were stained with Congo red and antilactoferrin antibody. The postoperative prognosis also was determined. MAIN OUTCOME MEASURES Clinical appearance of the 3 types of SCA, along with the gender, age, and duration of the basic diseases were determined. RESULTS Classification of SCA into 3 types based on clinical appearance found 21 cases with gelatinous drop-like dystrophy (GDLD)-like appearance (GDLD type), 3 cases with lattice corneal dystrophy (LCD)-like appearance (LCD type), and 5 cases with the combined type. Patients with the GDLD type were younger (average age: 40.9 years for the GDLD type, 74.3 years for the LCD type, and 46.8 years for the combined type), predominantly women (85.7% for the GDLD type, 33.3% for the LCD type, and 60% for the combined type), and had the basic disease over a longer time (average duration: 22.1 years for the GDLD type, 14.0 for the LCD type, and 11.4 for the combined type). The distribution of the basic diseases (trichiasis vs. keratoconus vs. unknown) was not significantly different for each type. Surgical treatments, for example, phototherapeutic keratectomy, lamellar keratoplasty, and simple keratectomy, resulted in a good resolution in all surgically treated cases. One subject dropped out of the study. Spontaneous resolution was seen in one subject after epilation of the cilia. Amorphous materials in the excised tissues showed positive staining results by Congo red and by antilactoferrin antibody. CONCLUSIONS Secondary corneal amyloidosis can be classified into 3 clinical types based on its clinical appearance. Larger numbers of females and lactoferrin expression were seen in all 3 types. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.