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Letters to the Editor TABLE 1. HLA tissue typing Patient I/1 I/2 I/3 II/1 II/2 II/3 II/4 357 The authors have declared no conflicts of interest. A B Cw DRB1 1/11 1/2 2/11 2/30 2/30 2/30 26/30 51/57 14/57 18/51 8/62 8/41 8/62 8/38 2/6 6 07/11 07/11 11 04 04/13 04 04/13 3 3 I/1, father; I/2, daughter; I/3, healthy sister. II/1, younger sister; II/2, her healthy daughter; II/3, older sister; II/4, her healthy son. she was treated with local CS for keratoconjunctivitis. Her father died at the age of 59 yr of pulmonary cavitation. Admission laboratory data showed creatinine 180 mol/l, perinuclear (p)ANCA antimyeloperoxidase (anti-MPO) positive (72.66 U/ml) and erythrocyturia. A chest X-ray showed diffuse interstitial thickening. An RB showed a pauci-immune crescentic GN. The patient was diagnosed with microscopic polyangiitis (MPA) with renal, lung, eye, skin and musculoskeletal involvement. Treatment with CS and CYC led to remission, creatinine decreased to 112 mol/L. This patient’s sister (56 yr old) had suffered from polyarthralgia, fever and anorexia for 2 months prior to admission in October 2004. Her erythrocyturia persisted after antibiotic treatment. The initial work-up revealed creatinine 160 mol/l and p-ANCA anti-MPO positive (41.72 U/ml). Chest X-ray was negative. An RB confirmed the diagnosis of MPA. Induction therapy with CS and CYC led to remission, creatinine dropped to 81 mol/l. This observation illustrates the diversity of the AAV determined by the sites and the activity/chronicity of organ involvement. Generalized ‘flu-like’ manifestation, ENT or respiratory symptoms lead mostly to antibiotic treatment. The detection of erythrocyturia often prompts another course of antibiotics and/or urological work-up. A temporary spontaneous remission of the symptoms further delays the diagnosis. As the disease persists, it may start to resemble a malignancy. Nevertheless, an erroneous diagnosis of carcinoma in the setting of a histological diagnosis of cutaneous vasculitis is a grave mistake. However varied the AAV may be, their clinical presentation in the two families described was in some aspects very similar. Both the father and daughter had WG, c-ANCA and a history of ENT involvement that preceded dialysis-requiring renal failure with some corresponding features in renal histology. The two sisters both had MPA, p-ANCA, nonspecific constitutional symptoms and histological and laboratory evidence of a rather slower decline in the renal function. We were unable to obtain objective data on their father. Nevertheless, the daughters described a suggestive picture of a pulmonary involvement in AAV. The difference in the presentation in the two families shows that PR3-ANCA and MPO-ANCA are markers of different diseases within the spectrum of AAV with a more acute presentation of patients with PR3-ANCA [1–3]. Last, but not least, the presented case reports raise the question of a familial predisposition to AAV. A number of familial cases have been described. A shared environment with exposure to silica has been thought to explain the cluster occurrence in some [4], whereas others have stressed the genetic predisposition [5, 6]. No consistent HLA association has been identified. Our patients within the two families shared a similar genetic background (Table 1). As mutations in the gene encoding -1 antitrypsin (AAT) are more frequent in patients with AAV [7], we tested all our patients and found their AAT levels to be within the normal range. Our patients did not share the same environment. The fact that two members of the two families fell ill with the same disease and their similar HLA typing seem to favour the role of a genetic predisposition to AAV. Z. RIHOVA, E. HONSOVA1, J. ZAVADA, Z. VANKOVA, E. JANCOVA, J. REITEROVA, V. TESAR Nephrology Unit, 1st Medical Faculty, Charles University and 1 Pathology Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Accepted 15 November 2005 Correspondence to: Z. Rihova, U Nemocnice 2, 128 08 Prague 2, Czech Republic. E-mail: [email protected] 1. Franssen CFM, Gans ROB, Arends B et al. Differences between antimyeloperoxidase and anti-proteinase 3 associated renal disease. Kidney Int 1995;61:80–9. 2. Hauer HA, Bajema IM, Van Houwelingen HC et al. Renal histology in ANCA-associated vasculitis: differences between diagnostic and serologic subgroups. Kidney Int 2002;61:80–9. 3. Franssen CFM, Gans ROB, Kallenberg CGM et al. Disease spectrum of patients with antineutrophil cytoplasmic antibodies of defined specificity: distinct differences between patients with anti-proteinase 3 and anti-myeloperoxidase autoantibodies. J Intern Med 1998; 244:209–16. 4. Brener Z, Cohen L, Goldberg SJ et al. ANCA-associated vasculitis in Greek siblings with chronic exposure to silica. Am J Kidney Dis 2001;30:E28. 5. Hull CM, Couser WG, Knostman JD. A familial case of p-ANCA glomerulonephritis presenting in a father and daughter. Am J Kidney Dis 2000;35:E23. 6. Nowack R, Lehmann H, Flores-Suarez LF et al. Familial occurrence of systemic vasculitis and rapidly progressive glomerulonephritis. Am J Kidney Dis 1999;34:364–73. 7. Callea F, Gregorini G, Sinico A et al. Alpha 1-antitrypsine (AAT) deficiency and ANCA-positive systemic vasculitis: genetic and clinical implications. Eur J Clin Invest 1997;27:696–702. Rheumatology 2006;45:357–359 doi:10.1093/rheumatology/kei264 Advance Access publication 20 December 2005 Infliximab treatment in a patient with rheumatoid arthritis on haemodialysis SIR, Anti-tumour necrosis factor (TNF) has been shown to be very effective in rheumatoid arthritis (RA). Patients with RA with renal failure are difficult to treat. Special attention is required to the possible increase in toxicity and to dose adjustment of the drugs used to treat this disease. We report our experience in treating such a patient with infliximab, a monoclonal TNF antagonist. A 45-yr-old female university professor presented in April 2002 with a 2-month history of painful and swollen joints of the small joints of both hands, wrists, knees, elbows and shoulders associated with morning stiffness of 2–3 h duration. In 1984 she was diagnosed with chronic glomerulonephritis of no obvious cause and in 1985 she had cadaveric renal transplant. The transplanted kidney was removed in 1995 because of chronic rejection and since then she has been on regular haemodialysis. In 1996 she was found to have hepatitis C, with a positive polymerase chain reaction (PCR) test, and was treated with interferon for 6 months. The PCR test became negative at the end of 6 months of therapy. One year later the liver enzymes increased again and the hepatitis C PCR test became positive at a high titre. She was again given interferon for 1 yr, which normalized the liver enzymes. Liver biopsy done in 1999 showed changes of very early fibrosis only. The patient has severe allergic reaction to sulpha drugs in ß The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected] Letters to the Editor childhood and had had marked hypertrichosis during treatment with cyclosporin associated with her kidney transplant. Physical examination showed very tender and swollen MCPs, PIPs, wrists, elbows, knees and shoulders. Laboratory investigations revealed positivity for rheumatoid factor of 320 IU, CRP 96 mg/dl, ANA 1:160, and negativity for anti-double-stranded DNA antibodies. Her ESR was 105 mm/h and haemoglobin was 9.7 gm/dl. She was treated with small doses of steroids and non-steroidal anti-inflammatory drugs (NSAIDs) but the response was inadequate. She frequently required joint aspiration and local steroid injection in different joints. She was tested for anti-cyclic citrullinated peptides in April 2004 and was positive, at more than 100 U. In May 2004 she presented with an acute flare, with very painful, swollen joints of the hands, both wrists, shoulders and the knees. Her ESR was 93 mm/h and CRP was 96 mg/l. The use of infliximab was discussed with the patient and this drug was given at 3 mg/kg at 0, 2 and 6 weeks, and then every 8 weeks. The arthritis improved remarkably with dramatic reduction of pain, swelling and improvement of the functional status. After the initial two infusions she developed post-infusion transient itching that responded to cetirizine 10 mg daily. When she was seen in December 2004 she had no significant stiffness but still had mild swelling of the both knees with little pain. Her ESR was 34 mm/h and CRP was 28 mg/dl. She was maintained on infliximab infusions every 8 weeks. The literature contains little information on the treatment of RA in patients with end-stage renal failure who are on haemodialysis. The potential toxicity of the drugs used, such as NSAIDs and disease-modifying drugs, deserves special attention. NSAIDs expose dialysis patients to an increased risk of gastroduodenal ulceration and bleeding, and it is advised that their use should be limited to short courses [1]. Methotrexate, which is the most commonly used drug and one of the most effective drugs in RA, is cleared primarily by the kidney and has been associated with life-threatening complications in a patient on haemodialysis who was on a small dose [2]. Azathioprine may be used but the dose should be reduced by 50% if the glomerular filtration rate is less than 10% [3]. In haemodialysis the drug was found to be effectively eliminated, suggesting that the dose of azathioprine can be maintained if the patient is on haemodialysis [4]. The hydroxychloroquine dose should be reduced by 50% in renal impairment [3]. Renal failure predisposes to a higher incidence of myopathy, neuropathy and cardiac myotoxicity in patients on hydroxychloroquine [5]. Cyclosporin may be given to patients with renal impairment on haemodialysis, at the same dose for patients with normal renal function [3]. A patient with bone marrow aplasia during haemodialysis was reported to improve after treatment with cyclosporin while he was on dialysis [6]. Leflunomide may be used in patients on haemodialysis and reduction of the dose does not appear to be required [7]. There are no reports or standards for the use of sulphasalazine in haemodialysis patients. However, Akiyama et al. reported the pharmacokinetics of this drug in a gastrectomized patient on haemodialysis who also had amyloidosis, and found that the drug metabolites did not differ from those in healthy controls during the 5 days after drug administration [8]. Anti TNF- is a new category of drug used in the treatment of RA, but very little is known about its use in renal impairment or in haemodialysis. The three available TNF antagonist are etanercept, infliximab and adalimumab. Infliximab is a chimeric monoclonal antibody composed of the human constant region and murine variable region. Singh et al. reported a patient with RA who failed to respond to treatment with several DMARDs and responded well to infliximab [9]. Yee et al. reported the use of infliximab in complicated sarcoidosis in a patient who required haemodialysis during the course of the disease [10]. Although the patient’s symptoms improved, the clinical course was complicated by the development of a hypercoagulable state, which improved after discontinuation of infliximab therapy. Ortiz-Santamaria et al. [11] reported the use of infliximab in six patients with amyloidosis (related to RA in five cases and to ankylosing spondylitis in one). Two of the six patients were on haemodialysis; one developed transient pancytopenia concurrently with renal function impairment and the infliximab was withdrawn. The other patient did not have any adverse event but the infliximab therapy was interrupted because at that time it was not known whether infliximab therapy could be administered to end-stage renal failure patients requiring haemodialysis. Searching the literature, we could not find any other reported cases of the use of other antagonists in rheumatoid patients with renal failure on haemodialysis. Our patient, like the patient of Singh et al., responded very well to treatment with infliximab and was able to return to her activities. She tolerated the drug well and did not show any unusual side-effects, which suggests that patients on haemodialysis can tolerate this drug and that the drug maintains its efficacy. The exact pharmacokinetics of infliximab in patients on dialysis are not known. However, in patients with normal renal function, infliximab has the lowest volume of distribution among the available TNF antagonists, which indicates that the distribution of infliximab outside the blood circulation and the inflamed tissue is limited [12]. Our case and the case of Singh et al. demonstrate the potential use of infliximab and possibly other anti-TNF biologicals in the treatment of rheumatoid patients with end-stage renal failure on haemodialysis. Key messages Rheumatology 358 Infliximab was effective and safe as monotherapy in a patient with RA on haemodialysis. The author has declared no conflicts of interest. M. HAMMOUDEH Rheumatology, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar Accepted 18 November 2005 Correspondence to: [email protected] 1. Bardin T, Kuntz D. Dialysis arthropathy. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatology, Vol. 2, 3rd edn. Pittsburgh: Mosby, 2003:1983–6. 2. Boulanger H, Launay-Vacher V, Hierniaux P, Fau JB, Deray G. Severe methotrexate intoxication in a hemodialysis patient treated for rheumatoid arthritis. Nephrol Dial Transplant 2001;16:1087. 3. Aronoff GR, Brier M. Prescribing drugs in renal disease. In: Brenner BM, ed. Brenner and Rector’s The Kidney, Vol. 2. 7th edn. Philadelphia: Saunders, 2004:2850–70. 4. Schusziarra V, Ziekursch V, Schlamp R, Siemensen HC. Pharmacokinetics of azathioprine under hemodialysis. Int J Clin Pharmacol Biopharm 1976;14:298–302. 5. Stein M, Bell MJ, Ang LC. Hydroxychloroquine neuromyotoxicity. J Rheumatol 2000;27:2927–31. Letters to the Editor 6. Vega J, Rodriguez M de L, Vasquez A, Torres C. Bone marrow aplasia during hemodialysis successfully treated with cyclosporin. Report of one case. Rev Med Chil 2004;132:989–94. 7. Beaman JM, Hackett LP, Luxton G, Illett KF. Effect of hemodialysis on leflunomide plasma concentrations. Ann Pharmacother 2002;36:75–7. 8. Akiyama Y, Fujimaki T, Sakurai Y. Pharmacokinetics of salazosulfapyridine in a hemodialysis patient. Ryumachi 2003;43: 569–76. 9. Singh R, Cuchacovich R, Huang W, Espinoza L. Infliximab treatment in a patient with rheumatoid arthritis on hemodialysis. J Rheumatol 2002;29:636–7. 10. Yee AM, Pochapin MB. Treatment of sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med 2001;135:27–31. 11. Ortiz-Santamaria V, Valls-Roc M, Sanmari M, Olive A. Anti-TNF treatment in secondary amyloidosis. Rheumatology 2003;42:1425–6. 12. Nestrov I. Clinical pharmacokinetics of tumor necrosis factor antagonists. J Rheumatol 2005;74:13–8. Rheumatology 2006;45:359–360 doi:10.1093/rheumatology/kel006 Advance Access publication 25 January 2006 Bronchogenic carcinoma associated with rheumatoid arthritis: role of FDG-PET scans SIR, Lung involvement occurs in 50% of patients with rheumatoid arthritis (RA). Its forms are variable, pulmonary nodules being the least frequent [1]. It is occasionally necessary to establish a differential diagnosis between rheumatoid nodules (RN) and bronchogenic carcinoma (BC), especially in smokers or immunocompromised patients [1]. There are no clinical or laboratory data to help with this differentiation and imaging techniques are not specific enough, which is why histological confirmation is recommended, either by bronchoscopy, transthoracic fine-needle aspiration (TFNA) or even surgical biopsy [2]. Positron emission tomography using 18-fluorodeoxyglucose (FDG-PET) is a noninvasive technique permitting the qualitative and semiquantitative analysis of tissue metabolic activity, which is increased in BC, and 359 which can guide the diagnosis of a suspected malignant pulmonary nodule in a patient with RA [3, 4]. We describe two RA patients with pulmonary nodules in which FDG-PET allowed the diagnosis and staging of BC, avoiding diagnostic surgical lung biopsy. The first case was a 64-yr-old woman, a non-smoker, diagnosed with seropositive RA in functional class I, undergoing treatment with methotrexate (7.5 mg/week). The physical examination showed mechanical pain and articulate tumefaction in the wrists and metacarpal phalanges. Chest X-ray and computed tomography (CT) revealed a nodule measuring 2.1 cm located in the upper right lobe. Bronchoscopy and TFNA were not conclusive. FDG-PET discovered abnormal increased activity corresponding to the location of the pulmonary nodule and hilar region, so BC was suspected (Fig. 1). Video-assisted thoracoscopy (VAT) biopsy of the nodule confirmed BC, so a right upper lobectomy and lymphadenectomy was performed. The definitive histology was infiltrant adenocarcinoma over an RN with mediastinal nodule involvement (T2N2M0). The postoperative course was satisfactory and the patient received adjuvant chemo-radiotherapy. The second case was a 40-yr-old male, a smoker (30 cigarettes/ day) diagnosed with seropositive RA in functional class II. Treatment was carried out combining methotrexate (7.5 mg/week) with leflunomide (20 mg/day). A chest X-ray and CT confirmed bilateral pulmonary nodules, one of them measuring 1.9 cm, in the left upper lobe, which bronchoscopy showed was positive for BC. FDG-PET was done to discard metastases in the rest of the nodules, and showed abnormal increased FDG activity corresponding only to BC. An upper left lobectomy and biopsies of the left lower lobe nodules were done. The definitive histology was infiltrant adenocarcinoma (T2N1M0) and the biopsies of the lower pulmonary nodules confirmed RN. The appearance of a pulmonary nodule in a patient with RA creates a diagnostic dilemma between RN and BC [1, 5]. Pulmonary RN are found in 1% of chest X-rays and up to 20% in high-resolution CTs [2]. It is frequent in males and smokers with subcutaneous RN and positivity for rheumatoid factor [1, 2]. Its radiological characteristics are not very specific, with central cavitation in 50% of cases [2]. They are usually asymptomatic and do not require treatment, except when there are complications such as bronchopleural fistula or infection, which are present in up to 50% of cases [2]. The possibility of developing BC in patients with RA is higher than in the general population, and the most FIG. 1. FDG-PET image showing abnormally increased FDG activity corresponding to the right upper pulmonary nodule visualized on the chest CT scan. ß The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]