ARCH SOC ESP OFTALMOL 2006; 81: 193-198

ORIGINAL ARTICLE

SYSTEMIC AUTOIMMUNE DISEASE IN PATIENTS WITH UVEITIS ENFERMEDAD AUTOINMUNE SISTÉMICA EN PACIENTES CON UVEÍTIS CARBONE J1, SARMIENTO E2, MICHELOUD D2, RODRÍGUEZ-MAHOU M3, RODRÍGUEZ-MOLINA JJ4, COBO R5, FERNÁNDEZ-CRUZ E1

ABSTRACT

RESUMEN

Objective: A descriptive study was conducted on patients with uveitis to determine the frequency of associated autoimmune systemic diseases. Methods: 64 patients with uveitis were studied. The patients were not known to have an underlying autoimmune systemic disease prior to the diagnosis of uveitis. All patients had the following immunological tests performed: serum immunoglobulins, complement components, circulating immune complexes (CIC), antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), anticardiolipin antibodies (ACA) and major histocompatibilty complex antigens. Results: A relationship with a sub-clinical autoimmune systemic disorder could be presumed in eleven cases (17.2%). This was defined by positive autoantibodies (ANA, ANCA or ACA) in the presence of complement consumption, hyper-gammaglobulinemia or increased CIC without clinical criteria of a defined autoimmune disease. A definite

Objetivo: La realización de un estudio descriptivo en pacientes con uveítis para establecer la frecuencia de enfermedad autoimmune sistémica asociada. Métodos: Se incluyeron en el estudio 64 pacientes con uveítis. Ninguno de los pacientes estudiados tenia una enfermedad autoinmune sistémica conocida antes del diagnóstico de uveítis. A todos los pacientes se les realizó un protocolo diagnóstico que incluyó las siguientes pruebas inmunológicas: inmunoglobulinas séricas, factores del complemento, inmunocomplejos circulantes (ICC), anticuerpos antinucleares (ANA), anticuerpos anticitoplasma de neutrófilos (ANCA), anticuerpos anticardiolipina (ACA) y antígenos del complejo mayor de histocompatibilidad. Resultados: En once casos (17,2%) se objetivó asociación con un proceso autoinmune subclínico caracterizado por la positividad de autoanticuerpos (ANA, ANCA o ACA) en presencia de consumo de complemento, hipergammaglobulinemia o ICC ele-

Received: 29/4/05. Accepted: 17/4/06. Clinical Immunology Unit. Immunology Service. Gregorio Marañón General University Hospital. Madrid. Spain. 1 Ph.D. in Medicine. 2 Graduate in Medicine. 3 Ph.D. in Biological Sciences. 4 Graduate in Biological Sciences. 5 Ph.D. in Medicine. Ophthalmology Service. Partially presented in the 27th Congress of the Spanish Immunology Society (Madrid, 2001) and in the 3rd International Congress of Autoimmunity (Geneva 2002). Correspondence: Javier Carbone Unidad de Inmunología Clínica. Servicio de Inmunología Hospital General Universitario Gregorio Marañón C/. Doctor Esquerdo, 46 28007 Madrid Spain E-mail: [email protected]

CARBONE J, et al.

association with systemic autoimmune disease was defined in four patients (6.25%). The observed autoimmune systemic diseases were Sjögren’s syndrome (n=2, 3.13%), anti-phospholipid syndrome associated with lupus-like disease (n=1, 1.6%), and systemic vasculitis (n=1, 1.6%). Lupus-like disease (n=4, 6.25%) was also observed. Conclusion: In a significant proportion of patients with uveitis an autoimmune systemic disorder may be present and should be looked for (Arch Soc Esp Oftalmol 2006; 81: 193-198). Key words: Uveitis, systemic autoimmune disease, lupus.

vados, sin que los pacientes cumpliesen criterios clínicos de una enfermedad autoinmune. Se encontró una asociación definitiva con enfermedad autoimmune sistémica en cuatro pacientes (6,25%). Las enfermedades autoinmunes observadas fueron el síndrome de Sjögren (n=2, 3,13%), síndrome antifosfolípido asociado a enfermedad lupus like (n=1, 1,6%) y vasculitis sistémica (n=1, 1,6%). También se observó un grupo de pacientes con enfermedad lupus like (n=4, 6,25%). Conclusión: En una proporción de pacientes con uveítis puede existir un proceso autoimmune sistémico subyacente. Palabras clave: Uveítis, enfermedad autoinmune sistémica, lupus.

INTRODUCTION Uveitis comprises a group of eye inflammatory diseases which affect the middle layers of the eye: the iris, the ciliar body and the choroids (1,2). Although the etiology is unknown in most cases, some patients may have an underlying systemic disease including infectious and autoimmune diseases (35). In this work we investigated the prevalence of the underlying systemic autoimmune disease in patients with uveitis, after carrying out an immunological study.

SUBJECTS, MATERIAL AND METHODS A retrospective study was made of 64 patients diagnosed with uveitis from the Ophthalmology Service and other services of the hospital. The demographic and clinical characteristics of the patients are shown in table I. In all cases, the diagnosis of uveitis was established in the referring services on the basis of the clinical records, ophthalmological exploration and complementary tests. The immunological, clinical and laboratory alterations exhibited by patients in association with uveitis were studied.

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Table I. Demographic and Clinical Characteristics of 64 patients with uveitis Parameter Gender Men Women Age (in years), mean (interval) Localization of uveitis Anterior Posterior Intermediate Panuveitis Unilateral Bilateral Number of episodes One Two > Two Treatment Topical corticoids Systemic corticoids Cyclosporine Treatment length < three months > three months Associated ophthalmological complications Vitreous hemorrhage Sinechiae Papillar edema Papillitis Retina detachment Retina thrombosis Optical atrophy Vasculitis

ARCH SOC ESP OFTALMOL 2006; 81: 193-198

Number (%) 33 (52) 31 (48) 42 (19-78) 38 (59.4) 14 (21.9) 4 (6.3) 8 (12.5) 59 (92.2) 5 (7.8) 46 (71.9) 15 (23.4) 3 (4.7) 24 (37.5) 24 (37.5) 54 (84.4) 10 (15.6) 6 (9.4) 10 (15.6) 2 (3.1) 3 (4.7) 3 (4.7) 2 (3.1) 1 (1.6) 1 (1.6)

Systemic self-immune disease in patients with uveitis

Self immunity study The detection of antinuclear antibodies (ANA) was performed by means of the indirect immunofluorescence technique (IFI) on HEp-2 cells (BION, Germany); the anti-DNA double chain antibodies and the extractable nuclear anti-antigen antibodies (anti-ENA) were studied by means of the ELISA technique; the neutrophile anti-cytoplasmic antibodies (ANCA) were studied by means of the IFI technique utilizing neutrophiles fixed in ethanol and subsequently by means of the ELISA anti-cardiolipine antibodies technique (ACA of isotypes IgG and IgM), anti-myeloperoxidase antibodies (anti-MPO) or anti-proteinase-3 (anti-PR3); the anticardiolipine antibodies were made by means of the ELISA technique dependent on beta-2-glicoprotein-I (Orgentec Diagnostika GmbH, Mainz, Germany); the rheumatoid factor (RF) was studied by means of the nephelometry technique (Beckman Coulter Izasa, California, USA).

The patients exhibiting positive autoantibody (particularly ANA, ANCA or ACA), evidence consumption of complement (low C3, C4 or CH100 numbers) and hypergammaglobuline or high ICC, in the absence of clinical criteria for connectivopathy, the presence of a sub-clinical self-immune process was considered (6). The patients who fulfilled 4 criteria of the American Rheumatology Academy for classification of Systemic Erithematose Lupus (LES) were classified as such (7). The patients fulfilling three of said criteria were considered to be Lupus-like Disease (LLD). Other systemic autoimmune diseases were diagnosed according to the criteria valued at the time of performing the diagnostic protocol.

RESULTS

The serum levels of inmunoglobuline (IgG, IgA, IgM), and complement factors (C3, C4 and Factor B) were determined by nephelometry technique (Beckman Coulter Izasa, California,USA); the total hemolytic activity of the complement (CH100) was studied by radial immunodifusion (Binding Site Limited, Birmingham, UK) and circulating immune complexes (ICC) by C1q-dependent nephelometry essay (Dade Behring Nephelometer Analyser II, Marburg, Germany and Quidel, San Diego California,USA).

The majority of patients (61%) did not exhibit clinical data for systemic autoimmune disease. Table II shows predominant symptoms and signs in patients. Arthritis, mouth ulcers and lymphopenia were the most frequent clinical alterations. The global distribution of immunological alterations are presented in table III. The association with HLA class 1 and 2 antigens are shown in table 4. Anterior uveitis associated to HLA-B27(+) was observed in eight patients (12.5%). One patient had a presumed diagnostic for Vogt-Koyanagui-Harada syndrome and another one for birdshot retinochoroidopathy. Eleven patients (17.2%) had positive self antibodies together with evidence of consumption of complement, hypergammaglobulinemia or high ICC, without fulfilling clinical criteria to be classified as connectivopathy. The presence of these immunolo-

Histocompatibility antigen study

Table II. Associated symptoms and signs in 64 uveitis patients

Humoral immunity study

The Class 1 and 2 HLA system antigen study was performed by microlinfocyte toxicity serum technique. Other diagnostic tests Full blood counts, full urine analysis, basic biochemistry and serology. Other supplementary tests were made on patients exhibiting suspect clinical or laboratory data for systemic connectivopathy.

Associated symptoms and signs None Arthritis Sicca Moulth ulcers Rash Sacroileitis Hypoaccusy and Vitiligus Abortion Anemia Lymphopenia Trombopenia

ARCH SOC ESP OFTALMOL 2006; 81: 193-198

Number (%) 39 (60.9) 6 (9.4) 3 (4.7) 7 (10.9) 2 (3.1) 2 (3.1) 2 (3.1) 1 (1.6) 4 (6.3) 13 (20.3) 3 (4.7)

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An additional four patients were diagnosed with LLD (6.25%). Table V shows the clinical and immunological alterations observed in the four patients with systemic autoimmune disease and in the four patients with LLD. The four patients who had a systemic autoimmune disease associated had suffered anterior uveitis. Two of the four patients with LLD had anterior uveitis and two more an intermediate uveitis. Two patients exhibited LLD associated to sacroileitis, one of whom had the class one antigen HLA-B27 (table V).

Table III. Immunological alterations in 64 uveitis patients Parameters Hypergammaglobulinemia IgA IgG IgM Hypogammaglobulinemia IgA IgG IgM Hypocomplementemia C3 C4 CH100 bajo High circulating immunocomplexes Autoantibodies Antinuclear antibodies (title 1/40-1/320) Anticytoplasmic neutrophile antibodies Anticardiolipine IgG antibodies Anticardiolipine IgM antibodies Rheumatoid factor

Number (%) 3 (4.7) 7 (10.9) 5 (7.8) 6 6 3

(9.4) (9.4) (4.7)

6 (9.4) 14 (21.9) 17 (26.6) 27 (42.2)

DISCUSSION

14 (21.9) 5 (7.8) 7 (10.9) 8 (12.5) 4 (6.3)

gical alterations did not have a significant association with clinical parameters for localization of uveitis, treatment time or the appearance of ophthalmological complications (Chi-square test, p>0.05). A definitive association was detected with a systemic autoimmune process in four cases (6.25%). The age of patients with systemic connectivopathy was similar to that of the rest of patients. However, there was a significantly higher proportion of women (Fischer exact test p