Absence of Histologic Evidence of Synovitis in Patients With Gulf War Veterans’ Illness With Joint Pain C. DIAZ-TORNE, 1 H. R. SCHUMACHER, 2 X. YU, 3 C. GOMEZ-VAQUERO, 4 L. DAI, 5 L. X. CHEN, 2 G. CLAYBURNE, 6 E. EINHORN, 6 R. M. SACHDEVA, 6 J. A. SINGH, 7 AND F. PESSLER 8 Objective. An unexplained multisymptom illness, Gulf War veterans’ illness (GWVI), has been described among allied force veterans of the first Gulf War (1990 –1991). It has been proposed that some of its symptoms reflect an immune dysfunction, and rheumatologic symptoms including joint pain and stiffness are reported frequently. However, it is unknown whether synovial inflammation causes the articular symptoms. We examined synovial tissue from individuals with GWVI and joint pain for evidence of inflammation. Methods. We compared synovial biopsy samples from 6 individuals with GWVI and joint pain with samples from 9 clinically asymptomatic controls (hematoxylin and eosin [H&E] stains only) and biopsy samples or surgically obtained specimens from 10 patients with rheumatoid arthritis (RA) and 12 with osteoarthritis (OA). Inflammatory changes were quantified in H&E stained sections with a modified synovitis score by immunostaining for CD3, CD20, CD38, CD68, Ki-67, and von Willebrand factor, and with a composite inflammation score based on these markers. Results. Normal histology was seen in the GWVI specimens, except for mild focal lining hyperplasia and rare low-grade perivascular infiltrates in 1 specimen each. Mean  SEM synovitis scores were lowest and nearly identical in control (1.38  0.30) and GWVI specimens (1.41  0.29), intermediate in OA specimens (2.64  0.39), and highest in RA specimens (6.0  0.19). Likewise, inflammatory cells, cell division, vascular density, and composite inflammation score were lowest in the GWVI specimens. Conclusion. Despite significant joint pain, the GWVI synovia did not differ from normal controls. These results agree with other studies that have failed to document inflammatory or immunologic etiologies in GWVI. KEY WORDS. Fibromyalgia; Gulf War veterans’ illness; Synovium; Arthralgia. INTRODUCTION A complex of unexplained symptoms including fatigue, memory impairment, headache, respiratory symptoms, skin changes, and musculoskeletal pain and stiffness has been described among personnel returning from the first Persian Gulf War (August 1990 to June 1991) and has been termed Gulf War syndrome or Gulf War veterans’ illness (GWVI) (1). Musculoskeletal symptoms have been among the most frequent symptoms, and in one study rheumato- logic evaluation was the most frequent subspecialty con- sultation among 250 patients attending a clinical evalua- Supported in part by a collaborative research grant from Merck Research Laboratories. Dr. Pessler’s work was sup- ported by NIH training grants T32-AR-007442 and T32-CA- 09140. Dr. Singh’s work was supported by a VA Scholar Grant from the Center for Epidemiological and Clinical Re- search, Minneapolis VA Medical Center. 1 C. Diaz-Torne, MD (current address: Hospital de la Santa Creu I Sant Pau, Barcelona, Spain): Hospital Universitari de Bellvitge, Barcelona, Spain, and the Philadelphia VA Med- ical Center, Philadelphia, Pennsylvania; 2 H. R. Schuma- cher, MD, L. X. Chen, MD, PhD: Philadelphia VA Medical Center, and the University of Pennsylvania School of Med- icine, Philadelphia; 3 X. Yu, MD: Philadelphia VA Medical Center, Philadelphia, Pennsylvania, and the Traditional Chinese Medicine-Western Medicine Hospital, Cangzhou, Hebei, China; 4 C. Gomez-Vaquero, MD: Hospital Universi- tari de Bellvitge, Barcelona, Spain; 5 L. Dai, MD, PhD: Phil- adelphia VA Medical Center, Philadelphia, Pennsylvania, and Sun Yat-sen University, Guangzhou, China; 6 G. Clay- burne, BS, E. Einhorn, MD, R. M. Sachdeva, MD: Philadel- phia VA Medical Center, Philadelphia, Pennsylvania; 7 J. A. Singh, MD: University of Minnesota, Minneapolis; 8 F. Pessler, MD, PhD: The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania. Address correspondence to F. Pessler, MD, PhD, Division of Rheumatology, Children’s Hospital of Philadelphia, 3405 Civic Center Boulevard, Philadelphia, PA 19104. E-mail: pessler@email.chop.edu. Submitted for publication December 13, 2006; accepted in revised form February 2, 2007. Arthritis & Rheumatism (Arthritis Care & Research) Vol. 57, No. 7, October 15, 2007, pp 1316 –1323 DOI 10.1002/art.23006 © 2007, American College of Rheumatology ORIGINAL ARTICLE 1316