CURRENT ABSTRACTS

Vasculitis Secondary to Staphylococcal Protein A Immunoadsorption (Prosorba Column) Treatmentin Rheumatoid Arthritis . . . By Atul Deodhar, Everett Allen, Katja Daoud, and Ihab Wahba

Objective: Vasculitis is a rare complication of immunoadsorption treatment with staphylococcal Protein A (Prosorbacolumn). The prevalence, clinical characteristics, pathophysiology, treatment, and outcome of vasculitis secondary toimmunoadsorption treatment is not known.Methods: The authors describe a 57-year-old woman with rheumatoid arthritis (RA) resistant to methotrexate andetanercept, who developed severe leukocytoclastic vasculitis after the 9th weekly treatment with Prosorba column. Shedeveloped rapidly progressive crescentic glomerulonephritis and required treatment with cyclophosphamide andhigh-dose prednisone. Subsequently, renal function stabilized and RA remitted. Through the literature search and byreviewing information submitted to Cypress Biosciences Inc (manufacturer of Prosorba columns), available worldliterature on vasculitis secondary to Prosorba column treatment was compiled.Results: Immune complex deposition of staphylococcal Protein A (SPA)/SPA antibodies in the glomeruli precipitatedthe renal disease in our patient. Twenty cases of vasculitis (calculated prevalence, 1 per 400), 5 with internal organinvolvement, have been reported in patients treated with Prosorba column for thrombocytopenic purpura. Seven RApatients treated with Prosorba column developed vasculitis (prevalence, 7 per 400), 3 with internal organ involvement.Conclusions: Vasculitis secondary to staphylococcal Protein A immunoadsorption therapy occurs rarely and appears tobe related to development of SPA/SPA antibody immune complexes. Rheumatologists should be aware of thispotentially serious complication of the Prosorba column treatment for RA.Semin Arthritis Rheum 32:3-9. Copyright 2002, Elsevier Science (USA). All rights reserved.

Potential Mechanism of Action of Intra-articular Hyaluronan Therapy in Osteoarthritis: Are theEffects Molecular Weight Dependent? . . . By Peter Ghosh and Diego Guidolin

Background: Hyaluronan, or hyaluronic acid (HA), is the major hydrodynamic nonprotein component of joint synovialfluid (SF). Its unique viscoelastic properties confer remarkable shock absorbing and lubricating abilities to SF, while itsenormous macromolecular size and hydrophilicity serve to retain fluid in the joint cavity during articulation. HA restrictsthe entry of large plasma proteins and cells into SF but facilitates solute exchange between the synovial capillaries andcartilage and other joint tissues. In addition, HA can form a pericellular coat around cells, interact with proinflammatorymediators, and bind to cell receptors, such as cluster determinant (CD)44 and receptor for hyaluronate-mediated motility(RHAMM), where it modulates cell proliferation, migration, and gene expression. All these physicochemical andbiologic properties of HA have been shown to be molecular weight (MW) dependent.Objective: Intra-articular (IA) HA therapy has been used for the treatment of knee osteoarthritis (OA) for more than 30years. However, the mechanisms responsible for the reported beneficial clinical effects of this form of treatment remaincontentious. Furthermore, there are a variety of pharmaceutic HA preparations of different MW available for thetreatment of OA, but the significance of their MWs with respect to their pharmacologic activities have not been reviewedpreviously. The objective of the present review is to redress this deficiency.Methods: We reviewed in vitro and in vivo reports to identify those pharmacologic activities of HA that were consideredrelevant to the ability of this agent to relieve symptoms and protect joint tissues in OA. Where possible, reports wereselected for inclusion when the pharmacologic effects of HA had been studied in relation to its MW. In many studies,only a single HA preparation had been investigated. In these instances, the experimental outcomes reported werecompared with similar studies undertaken with HAs of different MWs.Results: Although in vitro studies have generally indicated that high MW-HA preparations were more biologically activethan HAs of lower MW, this finding was not confirmed using animal models of OA. The discrepancy may be partlyexplained by the enhanced penetration of the lower MW HA preparation through the extracellular matrix of thesynovium, thereby maximizing its concentration and facilitating its interaction with target synovial cells. However, thereis accumulating experimental evidence to show that the binding of HAs to their cellular receptors is dependent on theirmolecular size; the smaller HA molecular species often elicits an opposite cellular response to that produced by thehigher MW preparations. Studies using large animal models of OA have shown that HAs with MWs within the rangeof 0.5 � 106-1.0 � 106 Da were generally more effective in reducing indices of synovial inflammation and restoringthe rheological properties of SF (visco-induction) than HAs with MW � 2.3 � 106 Da. These experimental findings

Seminars in

Arthritis and RheumatismVOL 32, NO 1 AUGUST 2002

were consistent with light and electron microscopic studies of synovial membrane and cartilage biopsy specimensobtained from OA patients administered 5 weekly IA injections of HA of MW � 0.5 � 106-0.73 � 106 Da in whichevidence of partial restoration of normal joint tissue metabolism was obtained.Conclusions: By mitigating the activities of proinflammatory mediators and pain producing neuropeptides released byactivated synovial cells, HA may improve the symptoms of OA. In addition, HAs within the MW range of 0.5 �106-1.0 � 106 Da partially restore SF rheological properties and synovial fibroblast metabolism in animal models. Thesepharmacologic activities of HA could account for the reported long-term clinical benefits of this OA therapy. However,clinical evidence has yet to be described to support the animal studies that indicated that HAs with MW � 2.3 � 106

Da may be less effective in restoring SF rheology than HAs of half this size.Semin Arthritis Rheum 32:10-37. Copyright 2002, Elsevier Science (USA). All rights reserved.

Prevalence of Post-Traumatic Stress Disorder in Fibromyalgia Patients: Overlapping Syndromes orPost-Traumatic Fibromyalgia Syndrome? . . . By Hagit Cohen, Lily Neumann, Yehoshua Haiman,Michael A. Matar, Joseph Press, and Dan Buskila

Objectives: The primary aim of this study was to assess the frequency of post-traumatic stress disorder (PTSD) inpatients with the fibromyalgia syndrome (FMS). The influence of gender on measures of PTSD in fibromyalgia (FM)patients also was examined.Methods: Seventy-seven consecutive patients (40 women and 37 men) who fulfilled the criteria for FM were asked tocomplete questionnaires measuring the prevalence and severity of symptoms of PTSD, anxiety, and depression. Thesubjects were divided in 2 groups based on the presence or absence of PTSD symptoms.Results: In this study, 57% of the FM sample had clinically significant levels of PTSD symptoms. The FM patients withPTSD reported significantly greater levels of avoidance, hyperarousal, reexperiencing, anxiety, and depression than didthe patients without clinically significant levels of PTSD symptoms. The prevalence of PTSD among the FM patientsin this study was significantly higher than in the general population. Women with FM and PTSD reported a greaternumber of past traumatic events than did their male counterparts.Conclusions: The results represent the first comprehensive study applying structured clinical assessment of traumaexposure and PTSD to a group of FM patients. This study shows a significant overlap between FM and PTSD, accordingto the currently accepted diagnostic criteria for each.Semin Arthritis Rheum 32:38-50. Copyright 2002, Elsevier Science (USA). All rights reserved.

Clinical Manifestations and Outcome of Polyarthralgia Associated With Chronic LymphocyticThyroiditis . . . By Leonardo Punzi, Paolo Sfriso, Margherita Pianon, Franco Schiavon, RobertaRamonda, Franco Cozzi, and Silvano Todesco

Objectives: Arthralgia is among the most frequent musculoskeletal symptoms occurring in patients with chroniclymphocytic thyroiditis (CLT), often causing pain and physical impairment over extended periods of time. Our studyaims to characterize arthralgia and, in particular, polyarthralgia (PA) associated with CLT and to evaluate the influenceof thyroid replacement therapy.Methods: Of 130 patients affected with CLT attending the Division of Rheumatology for rheumatic complaints, theauthors sequentially selected 20 patients with PA without any known rheumatic diseases. Of these 20 patients, 8 wereeuthyroid, 2 hyperthyroid, and 10 hypothyroid. The last group had never undergone therapy for thyroid disease; then,they were treated with thyroxine and followed up for 24 months. Clinical assessment included the number of jointsaffected by pain (NAJ), the visual analogic scale of pain (VAS), the duration of PA (number of days), and the intakeof acetaminophen.Results: At baseline, the only correlations in the 20 patients with PA were between NAJ and antithyroid microsomalantibodies (r � .782; P � .001), thyroid stimulation hormone (r � .651; P � .001), and erythrocyte sedimentation rate(r � .511; P � 0.021), respectively. During follow-up, although symptoms improved in the 10 hypothyroid patientstreated with thyroxine, a statistical significance was reached only after 12 months.Conclusions: Patients with CLT may be affected with PA severely, even in absence of hypothyroidism. Replacementtherapy with thyroxine in hypothyroid patients with CLT induced a progressive but gradual improvement of symptoms.Semin Arthritis Rheum 32:51-55. Copyright 2002, Elsevier Science (USA). All rights reserved.

Th1/Th2 Cytokine Imbalance in Patients With Sjogren Syndrome Secondary to Hepatitis C VirusInfection . . . By Manuel Ramos-Casals, Mario Garcıa-Carrasco, Ricard Cervera, Xavier Filella, OlgaTrejo, Gloria de la Red, Vıctor Gil, Jose Ma Sanchez-Tapias, Josep Font, and Miguel Ingelmo

Objective: To investigate if the serum immunologic profile, as delineated by serum circulating levels of Th1/Th2cytokines and autoantibodies, is different in patients with Sjogren syndrome (SS) with and without hepatitis C virus(HCV) infection.

Methods: This study included 20 patients with HCV-related SS and 47 consecutive patients with primary SS. Allfulfilled 4 or more of the modified 1996 European criteria for SS. Serum levels of interleukin (IL)-2 (pg/mL), srIL-2(pM), tumor necrosis factor (TNF)-� (pg/mL), IL-6 (pg/mL), and IL-10 (pg/mL) were determined using enzymeimmunoassay. We also analyzed the following immunologic tests: anti-nuclear antibodies (ANA), anti-mitochondrialantibodies (AMA), anti–parietal cell antibodies (PCA), anti–smooth muscle antibodies (SMA), anti–liver-kidneymicrosome antibodies type-1 (LKM-1), anti–Ro/SS-A, anti–La/SS-B, rheumatoid factor (RF), complement factors (C3and C4), and cryoglobulins.Results: Of the 20 patients with HCV-related SS, 18 were women and 2 men (mean age, 66 years). Patients withHCV-related SS had a different cytokine profile compared with patients with primary SS, with higher circulating levelsof IL-6 (73.6 v 33.0 pg/mL, P � .045), IL-10 (6.7 v 3.1 pg/mL, P � .01), srIL-2 (124.6 v 72.7 pM, P � .001), and TNF-�(59.8 v 31.7 pg/mL, P � .003). The main immunologic features were ANA, detected in 75% of patients, RF in 63%,cryoglobulinemia in 50%, hypocomplementemia in 40%, SMA in 30%, PCA in 25%, anti–Ro/SS-A in 25%, AMA in20% and anti-La/SS-B in 16%. When compared with primary SS patients, those with HCV-related SS had a higherprevalence of AMA (20% v 2%, P � .025), hypocomplementemia (40% v 11%, P � .015), and cryoglobulinemia (50%v 12%, P � .003).Conclusion: Although chronic HCV infection may mimic the main clinical, histologic and immunologic features ofprimary SS, patients with HCV-related SS showed some differentiated characteristics, including a predominant Th2pattern and a higher frequency of cryoglobulinemia and hypocomplementemia (features closely related to HCV). Thissuggests that the SS observed in some HCV patients should be interpreted as one of the extrahepatic manifestations ofchronic HCV infection.Semin Arthritis Rheum 32:56-63. Copyright 2002, Elsevier Science (USA). All rights reserved.

Clinical Characteristics and Etiologic Factors of Premenopausal Osteoporosis in a Group of SpanishWomen . . . By Pilar Peris, Nuria Guanabens, Ma Jesus Martınez de Osaba, Ana Monegal, Luisa Alvarez,Francesca Pons, Inmaculada Ros, Dacia Cerda, and Jose Munoz-Gomez

Objectives: To analyze the clinical characteristics and the principal causes of osteoporosis in premenopausal women.Methods: This study included 52 osteoporotic premenopausal women ages 20-51 years (mean 36.2 � 7) who werereferred to an outpatient rheumatology department for osteoporosis evaluation. Bone mass assessment, automatedbiochemical profile, urinary calcium excretion, and bone marker assays were performed on all patients. Hormonalmeasurements were made when a specific etiology was not readily apparent. The diagnosis of osteoporosis was definedby the presence of atraumatic vertebral fractures and/or by densitometric criteria. Previous skeletal fractures, weight,height, body mass index (BMI), age at menarche, and family history of osteoporosis also were recorded.Results: Twenty-nine patients (56%) had idiopathic osteoporosis and 23 (44%) had secondary osteoporosis. Fifteen patients(29%) had vertebral fractures and 12 had previous peripheral fractures. Patients with secondary osteoporosis showed higherBMI (23.2 � 3 v 21.2 � 2, P � .02) and lower femoral Z-scores of bone mineral density (BMD) (�2.1 � 0.6 v �1.5 �0.9, P � .02) than those with idiopathic disease. The most frequent causes of secondary osteoporosis included Cushingsyndrome, pregnancy osteoporosis, and osteogenesis imperfecta. Nearly half of the patients (48%) with idiopathic osteopo-rosis had a family history of osteoporosis. In addition, 11 patients (38%) with idiopathic osteoporosis had associatedhypercalciuria. Except for an increase in urinary calcium excretion (248 � 53 v 143 � 47 mg/24 h, P � .0001), no othersignificant differences in the remaining variables analyzed were found between hypercalciuric and normocalciuric patientswith idiopathic osteoporosis.Conclusions: Idiopathic osteoporosis was the most frequent diagnosis of pre-menopausal osteoporosis in our unit. These patientsshowed lower BMI and higher femoral neck Z-scores than patients with secondary causes. A family history of osteoporosis andhypercalciuria were factors frequently associated with this disorder.Semin Arthritis Rheum 32:64-70. Copyright 2002, Elsevier Science (USA). All rights reserved.