Cutaneous lupus erythematosus and immunoreactivity in patients with Ro/SSA autoantibodies

Lupus erythematosus (LE) is a heterogenous autoimmune disorder with many different clinical presentations. Cutaneous lupus erythematosus (CLE) is subdivided into acute, subacute and chronic CLE. Population-based epidemiologic studies of CLE are lacking and the pathogenesis is not fully understood. A major target for the autoimmune response in lupus is the Ro52 antigen, and Ro/SSA autoantibodies are frequently found in sera from patients with lupus. The focus of this thesis has been to estimate the incidence and prevalence of subacute CLE (SCLE) in Stockholm, Sweden, to characterize Ro/SSA-positive patients, both clinically and serologically, and to study the skin as a target organ to learn more about the autoimmune inflammatory process. By studying serology-based registers of Ro/SSA autoantibody positive patients and by the use of questionnaires, we could estimate the incidence of Ro/SSA-positive SCLE to 0.7 per 100,000 persons per year and the prevalence to 6.2-14 per 100,000 persons. Self-reported photosensitivity was found in 54% of the Ro/SSA-positive patients and polymorphous light eruption was found to be more common than in the general population. Smoking was also more common. Serologic analysis using enzyme linked immunosorbent assay revealed higher levels of autoantibodies binding Ro52 and La antigens in CLE patients with systemic manifestations compared to those with the disease confined to the skin, indicating different pathogenetic mechanisms for different clinical presentations. The fine specificity of Ro/SSA could thus serve as a tool to reveal predisposed patients at risk of developing systemic disease. Furthermore, a prospective study of our cohort revealed a dynamic disease process in Ro/SSA-positive patients in a short perspective of two years, with the development of either a new or an additional autoimmune disease as well as drug induced SCLE. Immunohistochemical studies of skin biopsies revealed increased cytoplasmic and extracellular expression of the proinflammatory cytokine high mobility group box chromosomal protein 1 (HMGB1) in both spontaneously occurring as well as in photoprovoked lesions of CLE compared to normal controls. These findings imply that HMGB1 is involved in the inflammatory autoimmune process of CLE and may thus constitute a potential therapeutic target. We were also able to demonstrate TNFα and IL-1β expression in CLE lesions which together with HMGB1 can result in sustained inflammation in CLE. The Ro52 antigen was studied and found to be overexpressed in systemic LE (SLE) and Sjogren’s syndrome patients and to function as an E3 ligase regulating proliferation and apoptosis. Ro52 may thus hypothetically contribute to the autoantigenic load and induction of autoimmune B and T cell responses observed in Ro/SSA-positive CLE patients as well. In conclusion, SCLE is a rare subset of lupus but our data together with prevalence estimations for other subsets, show that CLE is probably a more prevalent disease than SLE. Guidelines of care based on our findings will include councelling concerning smoking cessation, sun-protection and avoidance of photosensitizing drugs. Our findings also demonstrate the importance of awareness of the manifestations Ro/SSApositive patients are at risk of developing, and underline the need for regular clinical follow-up for these patients. LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to in the text by their Roman numerals: I. A serology-based approach combined with clinical examination of 125 Ro/SSA-positive patients to define incidence and prevalence of subacute cutaneous lupus erythematosus K Popovic, F Nyberg, M Wahren-Herlenius, F Nyberg Arthritis Rheum 2007; 56: 255-264. II. Fine specificity of the Ro/SSA autoantibody response in relation to serological and clinical findings in 96 patients with self-reported cutaneous symptoms induced by the sun K Popovic, S Brauner, M Ek, M Wahren-Herlenius, F Nyberg Lupus. Accepted for publication. III. A prospective study of 102 anti-Ro/SSA positive patients: Two-year follow-up with clinical examination and questionnaires K Popovic, M Wahren-Herlenius, F Nyberg Submitted for publication. IV. Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus K Popovic, M Ek, A Espinosa, L Padyukov, H Erlandsson Harris, M WahrenHerlenius, F Nyberg Arthritis Rheum 2005; 52: 3639-3645. V. Extracellular and cytoplasmic translocatiom of HMGB1 coincides with the peak of clinical activity in experimentally UV-induced lesions of cutaneous lupus erythematosus V Barkauskaite, M Ek, K Popovic, H Erlandsson Harris, M WahrenHerlenius, F Nyberg Submitted for publication. VI. The Sjogren’s syndrome-associated autoantigen Ro52 is an E3 ligase that regulates proliferation and cell death A Espinosa, W Zhou, M Ek, M Hedlund, S Brauner, K Popovic, L Horvath, T Wallerskog, M Oukka, F Nyberg, VK Kuchroo, M Wahren-Herlenius J Immunol 2006; 176: 6277-6285. Copyright holders are acknowledged for permission to reprint the published articles in this thesis.