keh-letters 1310..1311

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Correspondence to: K. C. Harner, Walter Reed Army Medical. Center, Rheumatology Clinic, Ward 77, 6900 Georgia Avenue,. NW, Washington, DC 20307, USA.
Letters to the Editor

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TABLE 1. The patient’s aCL antibody titres (U/ml) before and after treatment with rituximab in January 2003 aCL antibody class

March 2001

July 2001

March 2003

October 2003

IgG IgM IgA

156.3 22.7 18.6

27.0 110.3 31.5

0.0 6.0 6.0

14.0 10.0 0.0

In 2001, positive IgG, IgM and IgA were >12.3, >12.9 and >16 U/ml, respectively. In 2003, positive IgG, IgM and IgA were 19, 10 and 15 U/ml, respectively.

profile consistent with the diagnosis (positive ANA, positive SSA/ SSB and positive high-titre RF). Initially, symptomatic treatment was successful. In 1995, the patient presented with left cervical lymphadenopathy, leading to a biopsy demonstrating marginal zone lymphoma (MALT). Staging bone marrow biopsy was negative, as were subsequent bone marrow biopsies. A right cervical lymph node excision in 1997 was consistent with MALT. In 2001, after presenting with acute pleuritic chest pain, the patient underwent evaluation for suspected pulmonary embolus. Imaging revealed a right common iliac deep venous thrombosis, without evidence of pulmonary embolus. Concurrent with the initiation of anticoagulation, an evaluation for a possible hypercoagulable state yielded positive aCL on two occasions. Lupus anticoagulant was negative on both occasions. She has continued on warfarin therapy for secondary APS without recurrent thromboembolic events to date. In 2002, the patient experienced recurrence of her pulmonary lymphoma by surveillance computed tomography (CT) and positron emission tomography (PET) scans. Upon surgical excision of this lesion, pathology again revealed marginal zone lymphoma. Due to continued recurrence of her lymphoma, rituximab was initiated in 2003 using a standard protocol. In addition to inducing stability of the lymphoma and decreasing her SS symptoms, rituximab normalized the patient’s previous high-titre ACL antibodies (Table 1). Follow-up CT and PET scans since administration of rituximab show no recurrence of disease. The patient will undergo a 2-yr maintenance regimen of rituximab at a minimum to continue to treat marginal cell lymphoma and her underlying connective tissue disease. In our patient, the normalization of aCL was fortuitous and not the reason for initiating rituximab therapy. To our knowledge, this is the first case report of such an association. We realize it is difficult to determine the cause of this patient’s deep venous thrombosis, which might have been either due to secondary APS (from underlying SS or lymphoma) or paraneoplastic, although the latter is rare. However, we feel that the high titre of the aCL is significant. In addition, we realize that aPL levels can vary over time, but such a dramatic decrease is probably due to the use of rituximab in this case. We feel that this case illustrates the effectiveness of rituximab in reducing high-titre aCL levels to a normal range. This finding, if validated by other case reports and trials, could have dramatic implications for the use of rituximab in treating and preventing complications due to APS, in particular catastrophic APS. In conclusion, rituximab could be used as primary therapy for this difficult syndrome. The views expressed in this case report are those of the authors and are not necessarily those of Walter Reed Army Medical Center, the Department of the Army, or the Department of Defense. The authors have declared no conflicts of interest. K. C. HARNER, L. W. JACKSON, J. J. DRABICK Walter Reed Army Medical Center, Washington, DC, USA Accepted 15 June 2004

Correspondence to: K. C. Harner, Walter Reed Army Medical Center, Rheumatology Clinic, Ward 77, 6900 Georgia Avenue, NW, Washington, DC 20307, USA. E-mail: kyle.harner@ na.amedd.army.mil 1. Kassan SS, Thomas TL, Moutsopoulos HM et al. Increased risk of lymphoma in sicca syndrome. Ann Intern Med 1978;89:888–92. 2. Asherson RA, Fei H, Staub HL, Khamashta MA, Hughes GRV, Fox RI. Antiphospholipid antibodies and HLA associations in primary Sjogren’s syndrome. Ann Rheum Dis 1992;51:495–8. 3. Ingram SB, Goodnight SH Jr, Bennet RM. An unusual syndrome of a devastating noninflammatory vasculopathy associated with anticardiolipin antibodies: report of two cases. Arthritis Rheum 1987;30:1167–72. 4. Onida P, Tresoldi M, Rugarli C. Anti-phospholipid-antibody syndrome associated with peripheral T-cell lymphoma. Am J Hematol 1997;55:167–8. 5. Ciaudo M, Horellou MH, Audouin J et al. Lupus anticoagulant associated with primary malignant lymphoplasmacytic lymphoma of the spleen: a report of four patients. Am J Hematol 1991;38:271–6. 6. Sciarra, Stasi R, Stipa E et al. Antiphospholipid antibodies: their prevalence, clinical significance and correlation with cytokine levels in acute myeloid leukemia and non-Hodgkin’s lymphoma. Recent Prog Med 1995;86:57–62. 7. Timuragaoglu A, Duman A, Ongut G, Saka O, Karadogan I. The significance of autoantibodies in non-Hodgkin’s lymphoma. Leuk Lymphoma 2000;40:119–22. 8. McGuire D, Zeidman A, Mittelman M. Non-Hodgkin’s lymphoma presenting with coagulopathy due to anti-phospholipid antibody syndrome. Leuk Lymphoma 1997;26:193–6. 9. Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum 2003;48:1484–92. 10. Somer BG, Tsai DE, Downs L, Weinstein B, Schuster SJ. Improvement in Sjogren’s syndrome following therapy with rituximab for marginal zone lymphoma. Arthritis Rheum 2003;49:394–8.

Rheumatology 2004;43:1310–1311 doi:10.1093/rheumatology/keh319

A case of successful pregnancy in a woman with systemic sclerosis treated with cyclosporin SIR, Systemic sclerosis (SSc) is a generalized connective tissue disease characterized by a strong female predilection. In our experience low-dose cyclosporin A (CyA) (1–3 mg/kg per day) provides a therapeutic option for patients with multivisceral involvement [1]. Its use during pregnancy in female transplant recipients has been proved to be safe, but there is little experience in autoimmune patients [2]. We present a case of successful pregnancy in a 25-yr-old woman with SSc who was treated with CyA. She presented to our department with severe Raynaud’s phenomenon attacks. Physical examination showed scleroderma skin changes proximal to the metacarpophalangeal joints and to the face. Mild restrictive lung disease associated with reduction of diffusion capacity for carbon monoxide, microvascular abnormalities (evaluated by nailfold videocapillaroscopy), a slight increase in renal vascular resistance and abnormal oesophageal motility were revealed by instrumental evaluation. Haematological parameters and urinalysis showed no significant abnormalities. Anti-topoisomerase 1 antibodies were positive. Anti-Ro (SSA), anti-La (SSB) and anticardiolipin antibodies were not found. Total functional haemolytic complement (CH 50) and C3 levels were decreased, while C4 level was normal.

Rheumatology Vol. 43 No. 10 ß British Society for Rheumatology 2004; all rights reserved

Letters to the Editor On the basis of these data, SSc was diagnosed and CyA (3 mg/kg per day) was started, together with omeprazole (20 mg/day) and courses of intravenous (i.v.) vasodilators: iloprost (1 ng/kg per min in a 6 h i.v. infusion, for 5 consecutive days, 1 week per month). The patient showed partial remission after 24 months of therapy with CyA. The drug was then tapered until complete suspension, but evidence of active disease after 6 months led to the restoration of immunosuppressive treatment, with improvement in the involved organ and no new disease-specific visceral damage. The patient strongly desired a baby and her disease appeared to be stabilized. Hence, she underwent a detailed gynaecological evaluation; no major contraindication to pregnancy was found and she was allowed to get pregnant, which she did 4 months after a second round of cyclosporin therapy. Prophylactic supplementation with iron and folic acid was administered. During pregnancy no serious complication occurred and the biochemical profile showed no significant pathological alterations. She stayed on immunosuppressive treatment with no dose modification, and no major sideeffects occurred. When the patient was 29 yr of age she delivered a girl (2.2 kg) at the 34th week, with Caesarean section. Pregnancy outcome was a preterm birth (according to ACOG definitions) [3]. The baby had no deformities. The mother did not breast-feed. Maternal clinical, biochemical and instrumental follow-up (24th month after pregnancy) showed no significant pathological modifications; the infant grew and developed normally. The frequency of maternal complications in SSc patients, either in diffuse or in limited form, is not increased compared with healthy controls, except for renal crisis [4]. This risk is lower if pregnancy is planned within 3–5 yr from onset of symptoms [5]. Our patient became pregnant when the duration of disease, considered to have started at the time of the onset of Raynaud’s phenomenon, was 8 yr and cutaneous and visceral manifestations were stable. The prevalence of delivery of premature or small infants has been reported to be increased: the underlying pathophysiological mechanisms remain unknown and standard obstetric problems, not strictly related to SSc, cannot be excluded [6]. Our data suggest an encouraging clinical effect for low-dose, long-term CyA treatment in SSc: tolerability and clinical improvement were observed in nine patients consecutively treated for at least 3 yr. Cyclosporin is currently administered to female organ transplant recipients, associated or not with azathioprine and steroids: their pregnancies are at high risk but most outcomes are favourable for mother and baby. Fewer than 100 cases of pregnancy in women with autoimmune diseases treated with CyA have been reported in the literature: most were rheumatoid arthritis patients [6]; there were few SLE patients [7]. To our knowledge this is the first report of successful pregnancy in an SSc patient treated with low-dose CyA. The authors have declared no conflicts of interest. M. BASSO, M. GHIO, G. FILACI, M. SETTI, F. INDIVERI Department of Internal Medicine, Faculty of Medicine, Genoa, Italy. Accepted 18 June 2004 Correspondence to: M. Ghio, Department of Internal Medicine, University of Genoa, Viale Benedetto XV/6, Genoa 16132, Italy. E-mail: [email protected] 1. Filaci G, Cutolo M, Basso M et al. Longterm treatment of patients affected by systemic sclerosis with cyclosporin A. Rheumatology 2001;40:1431–2. 2. Janssen NM, Genta MS. The effects of immunosuppressive and antiinflammatory medications on fertility, pregnancy, and lactation. Arch Intern Med 2000;160:610–9.

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3. Standard terminology for reporting of reproductive health statistics in the United States. Washington, DC: American College of Obstetricians and Gynecologists, 1987. 4. Steen VD. Pregnancy in women with systemic sclerosis. Obstet Gynecol 1999;94:15–20. 5. Steen VD. Pregnancy in systemic sclerosis. Rheum Dis Clin North Am 1997;23:133–47. 6. Ghandour FZ, Knauss TC, Hricik DE. Immunosuppressive drug in pregnancy. Adv Ren Replace Ther 1998;5:31–7. 7. Maeshima E, Yamada Y, Kodama N, Mune M, Yukawa S. Successful pregnancy and delivery in a case of systemic lupus erythematosus treated with immunoadsorption therapy and cyclosporin A. Scand J Rheumatol 1999;28:54–7.

Rheumatology 2004;43:1311–1313 doi:10.1093/rheumatology/keh280

The fibromyalgia problem. A Latin American point of view SIR, I read with interest the article by Hazemeijer and Rasker on fibromyalgia and the therapeutic domain [1] and the recent editorial comments by Harth and Nielson [2] and Wolfe [3]. Controversy about fibromyalgia as a ‘real’ or ‘false’ disease is frequent. Recently, an article on fibromyalgia in an Amish community by White and Thompson [4] had four accompanying editorials and points of views from Gordon, Ehrlich, Hadler, and again Wolfe [5–8]. I have also had the opportunity to read the recent articles by Gracely et al. [9] and Paiva et al. [10] and the editorial by Crofford and Clauw in a recent journal [11]. After a more than a decade of ACR criteria, controversies remain. Is fibromyalgia syndrome (FMS) really a disease? If it is, is it a rheumatological disease or a psychiatric or psychological disease? Are the current criteria useful? Moreover, is there something useful for these patients? FMS is a costly disease, which represents an economic problem for health care systems. Although chronic pain has always existed, since we started labeling it as FMS using the ACR criteria, work disability payments have grown up to 25.3% in developed countries [12, 13]. From my Latin American point of view, economic matters is one of the main reasons why, in developed countries, the rheumatological community is looking desperately for a cause and a marker for chronic widespread pain. Doctors need to justify diagnosis and disability in patients to the health care system and insurance companies in order for them to cover the costs of the disease. The Amish community is known for their absence of economic influences. High prevalence of FMS (7%) in this population attempts to ‘prove’ that the disease develops independently from economic matters [4]. However, the controversy is still open. Current candidates for disease markers could be the substance P level in the cerebrospinal fluid [14], neurohormonal alterations [15], dysautonomic dysfunctions [16], altered alpha sleep characteristics [17] and functional magnetic resonance imaging [18], which offers interesting data but incomplete or circumstantial explanations for disease. Furthermore, there is strong evidence that previous features of somatization contribute to the development of chronic widespread pain, and persons with FMS exhibit functional impairment, high levels of some lifetime and current psychiatric disorders, and significant psychological distress [18] labelling FMS as a ‘mind disease’ with rheumatic complaints, as Hazemeijer and Rasker point out in their philosophical study [1]. Current criteria take into account only the expression (tender points) and not the causes of pain. It is well known that pain can arise from the involvement of peripheral nerve fibres but also can arise from central nerve fibres. In the 1960s, Ronald Melzac proposed a gate theory whereby physical conditions (damage

Rheumatology Vol. 43 No. 10 ß British Society for Rheumatology 2004; all rights reserved