Determination of Lymphotoxin-Alpha Levels in Patients with Psoriatic Arthritis Undergoing Etanercept Treatment Giuseppe Murdaca, Barbara Maria Colombo, Paola Contini, and Francesco Puppo Tumor necrosis factor (TNF)-a plays a central role in psoriatic arthritis (PsA). A subgroup of patients with PsA do not respond to anti-TNF-a antibodies but respond to TNF receptor p75-Fc IgG fusion protein (etanercept), which also neutralizes lymphotoxin (LT)-a. It has been suggested that LT-a might be involved in the devel- opment of the disease. We determined LT-a serum levels in 15 PsA patients before (T0) and after 3, 6, 9, and 12 months of etanercept therapy (T3, T6, T9, and T12, respectively) and correlated them with their response to treatment. Bath Ankylosing Spondylitis Disease Activity Index, Psoriasis Area Severity Index, Disease Activity Score (DAS28), erythrocyte sedimentation rate (ESR), and C reactive protein (CRP) levels were assessed at the same time points. All patients showed a clinical response at T6, which persisted up to T12; ESR and CRP mean levels significantly decreased at T3 and remained within the normal range up to T12. LT-a levels significantly increased from T3 to T6 and returned to baseline levels at T12. Therefore, the LT-a serum levels do not seem to correlate with clinical and laboratory parameters of the response to etanercept in PsA patients. Further studies are required to better define the role of LT-a and LT-a blockade by etanercept in PsA patients. Introduction T umor necrosis factor (TNF)-a is a proinflammatory cytokine that plays an essential role in the pathogenesis of rheumatoid arthritis (RA) (O’Shea and others 2002). Ele- vated levels of this cytokine are detectable in the serum and synovial fluid of RA patients and correlate with markers of disease severity and activity. TNF-a inhibition with anti-TNF agents is associated with a good and sustained clinical re- sponse (Feldmann 2002). Lymphotoxin-a (LT-a or TNF-b) is a close homolog of TNF-a, as it exerts similar biological activi- ties and engages the same receptors (O’Shea and others 2002; Schneider and others 2004). However, although LT-a has been found in the synovial tissue of diseased joints, its role in ar- thritis is not well defined (Grom and others 1996). The neu- tralization of TNF-a and LT-a is naturally mediated by 2 soluble TNF receptors (TNFR), designated p55 (Type I) and p75 (Type II), whose levels increase in the serum and synovial fluid of RA patients in an attempt to counteract TNF-a excess (Cope and others 1992). Anti TNF-a monoclonal antibodies (infliximab and adalimumab) and a recombinant human di- meric TNFR p75-Fc IgG fusion protein (etanercept) have been developed for the therapeutic neutralization of TNF-a. Inter- estingly, only etanercept is able to neutralize LT-a. High levels of LT-a have been detected in the serum and synovial fluid of a subgroup of RA patients and, in partic- ular, in juvenile RA patients (Buch and others 2004). Of note, the clinical response to etanercept has been reported in 38% to 75% of subjects with RA after the failure of anti-TNF-a monoclonal antibody therapy (Di Poi and others 2007). It is known that TNF-a also plays an important role in the patho- genesis of psoriasis and psoriatic arthritis (PsA) and that both diseases respond to anti-TNF-a monoclonal antibodies (Mease 2005). Moreover, TNF-a/LT-a inhibition with etanercept down-regulates multiple proinflammatory cytokines, such as interleukin (IL)-1, IL-8, and IL-23, in psoriasis plaques (Gottlieb and others 2005). Among the PsA patients, there is a subgroup that does not respond to anti-TNF-a monoclonal antibodies but responds to etanercept (Conti and others 2007; Mazzotta and others 2009), suggesting that in these patients, LT-a might also play a role in the development of the disease. The aim of the present study was the determination of LT-a serum levels in patients affected by PsA before and during etanercept treat- ment and the correlation with their response to treatment. Materials and Methods Fifteen consecutive patients (8 women and 7 men; age 26–73 years) who had been affected by PsA, attending our outpatient clinic and eligible for etanercept treatment, were enrolled. In- clusion criteria were as follows: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ‡ 4, Psoriasis Area Severity Index (PASI) ‡ 20, Disease Activity Score (DAS28) > 5.1, and erythrocyte sedimentation rate (ESR) and/or C reactive pro- tein (CRP) level ‡ 2 times the normal range. Response criteria were as follows: BASDAI £ 2, PASI £ 10, DAS28 £ 3.2, and normalization of ESR and CRP levels. Etanercept was subcu- taneously given at a dose of 25 mg twice a week for 12 months. Department of Internal Medicine, University of Genoa, Genoa, Italy. JOURNAL OF INTERFERON & CYTOKINE RESEARCH Volume 32, Number 6, 2012 ª Mary Ann Liebert, Inc. DOI: 10.1089/jir.2011.0120 277