- Email: [email protected]
Rheumatoid arthritis, alveolar echinococcosis, and rituximab: A case report
Letters to the editor / Joint Bone Spine 79 (2012) 323–334
325
Table 1 Basic PDUS findings at all the entheseal sites examined in PsA and RA patients: prevalence, percentage (%) and grade (mean ± 95% CI). Prevalence and percentage (%) of basic PDUS findings Basic PDUS findings
PsA
RA
Hypoechogenicity Thickening Calcifications Enthesophytes Erosions Bony irregularity PD signal enthesis PD signal tendon Bursitis Tendon lesion
178 (16.7%) 72 (6.8%) 202 (19%) 391 (36.8%) 67 (6.3%) 126 (11.8%) 49 (4.6%) 64 (6%) 86 (8.1%) 5 (0.5%)
14 (3.8%) 19 (5.2%) 31 (8.5%) 107 (29.4%) 5 (1.4%) 53 (14.6%) 4 (1.1%) 12 (3.2%) 27 (7.4%) 1 (0.3%)
Grade of basic PDUS findings (mean ± 95%CI)
P
PsA 0.0000001 n.s 0.000003 0.011 0.0002 n.s 0.002 0.046 n.s n.s
0.2 0.1 0.3 0.5 0.08 0.12 0.07 0.1 0.01 0.04
P
RA ± ± ± ± ± ± ± ± ± ±
0.02 0.01 0.04 0.04 0.02 0.01 0.02 0.02 0.02 0.03
0.04 0.05 0.1 0.4 0.01 0.15 0.01 0.03 0.08 0.027
± ± ± ± ± ± ± ± ± ±
0.02 0.02 0.04 0.08 0.01 0.03 0.01 0.2 0.03 0.005
0.0001 n.s 0.0001 n.s 0.0001 n.s 0.002 0.009 n.s n.s
PDUS: power Doppler ultrasound; PsA: psoriatic arthritis; RA: rheumatoid arthritis; CI: confidence interval; PD: power Doppler.
2. Results One thousand and sixty-four entheses of 76 PsA patients and 224 of 26 RA controls were examined. The global number of entheses with PDUS-detected abnormalities (Fig. 1) were 756 in PsA patients and 224 in controls (P = 0.0008). At enthesis level, the prevalence and grade of most inflammatory and structural damage lesions (Table 1) resulted to be significantly higher in PsA than in RA (P < 0.0000001 and 0.01 respectively). The global entheseal PDUS score showed a more serious involvement in PsA than in controls (22.77 ± 18.8 vs 14.04 ± 9.8; P = 0.03). Poor significant correlations were demonstrated between global entheseal PDUS score and MASES (P < 0.033). The analysis of the findings at patient level didn’t give results able to discriminate between RA and PsA patients.
[8] Jacobs JC. Spondylarthropathy and enthesopathy. Arch Intern Med 1983;143:103–7. [9] McGonagle D, Gibbon W, Emery P. Classification of inflammatory arthritis by enthesitis. Lancet 1998;352:1137–40.
Annamaria Iagnocco a,∗ Antonio Spadaro a Antonio Marchesoni b Alberto Cauli c Orazio De Lucia b Alessandra Gabba c Silvia Takanen a Monica Montepaone a Fabio Massimo Perrotta a Maria Antonietta D’Agostino d Alessandro Mathieu c Guido Valesini a a Rheumatology Unit, Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Policlinico Umberto 1◦ , Viale del Policlinico 155, 00161 Rome, Italy b Rheumatology Department, Istituto Ortopedico Gaetano Pini, Milano, Italy c Rheumatology Department, Università di Cagliari, Cagliari, Italy d Department of Rheumatology, université Paris Ouest-Versailles-Saint-Quentin-en-Yvelines, hôpital Ambroise-Paré, AP–HP, 92100 Paris, France
3. Discussion This is the first study showing PDUS findings indicative of extensive and severe entheseal abnormalities, related both to inflammation and structural damage, in PsA. Enthesitis, a typical pathological feature of SpA, may assume variable aspects and different locations [7–9]. However, due to the low sensitivity of clinical assessment in the detection of inflammatory musculoskeletal changes, peripheral enthesitis is frequently mixed up with other joint and soft tissues disorders by physical examination and its presence may be often underestimated [1]. Therefore, imaging modalities, such as musculoskeletal US, play a fundamental role in this field helping in the detection of various entheseal abnormalities at different entheseal sites.
∗ Corresponding
author. Tel.: +39 06 49974637; fax: +39 06 49974642. E-mail address: [email protected] (A. Iagnocco)
Disclosure of interest
2 October 2011 Available online 26 November 2011
The authors declare that they have no conflicts of interest concerning this article. doi:10.1016/j.jbspin.2011.10.005
References [1] D’Agostino MA, Said-Nahal R, Hacquard-Bouder C, et al. Assessment of peripheral enthesitis in the spondylarthropathies by ultrasonography combined with power Doppler: a cross-sectional study. Arthritis Rheum 2003;48:523–33. [2] Riente L, Delle Sedie A, Filippucci E, et al. Ultrasound imaging for the rheumatologist IX. Ultrasound imaging in spondyloarthritis. Clin Exp Rheumatol 2007;25:349–53. [3] Filippucci E, Aydin SZ, Karadag O, et al. Reliability of high-resolution ultrasonography in the assessment of Achilles tendon enthesopathy in seronegative spondyloarthropathies. Ann Rheum Dis 2009;68:1850–5. [4] Balint PV, Kane D, Wilson H, et al. Ultrasonography of entheseal insertions in the lower limb in spondyloarthropathy. Ann Rheum Dis 2002;61:905–10. ˜ [5] De Miguel E, Cobo T, Munoz-Fernández S, et al. Validity of enthesis ultrasound assessment in spondylarthropathy. Ann Rheum Dis 2009;68:169–74. [6] Wakefield RJ, D’Agostino MA, Iagnocco A, et al. The OMERACT Ultrasound Group: status of current activities and research directions. J Rheumatol 2007;34:848–51. [7] McGonagle D, Khan MA, Marzo-Ortega H, et al. Enthesitis in spondylarthropathy. Curr Opin Rheumatol 1999;11:244–50.
Rheumatoid arthritis, alveolar echinococcosis, and rituximab: A case report夽
a r t i c l e
i n f o
Keywords: Alveolar echinococcosis Rituximab Rheumatoid arthritis
夽 The first two authors contributed equally to this manuscript.
326
Letters to the editor / Joint Bone Spine 79 (2012) 323–334
Table 1 Medications taken to treat rheumatoid arthritis and reasons for changes. Medication history Start date
End date
Medications
May 1996 June 1996 November 1996 June 1997 January 1998
May 1996 June 1996 October 1996 April 1997 January 1998 November 1998
Indomethacin Prednisone Penicillamine up to 900 mg/day + prednisone Methotrexate + prednisone Penicillamine + prednisone Aurothiopropanolsulfonate + prednisone
Reason for stopping
January 1999 May 1999 March 2001 May 2001 October 2002
May 1999 March 2001 April 2001 October 2002 October 2003
October 2003 July 2004 November 2005 March 2006
July 2004 November 2005 February 2006
Inadequately effective Inadequately effective Effective but proteinuria 1.17 g/24 h Inadequately effective Proteinuria starting at 900 mg/day Inadequately effective and adverse effects Methotrexate + prednisone + hydroxychloroquine Escape phenomenon Methotrexate + prednisone + hydroxychloroquine + sulfasalazine Inadequately effective Methotrexate + prednisone Not effective Methotrexate + prednisone + infliximab Escape phenomenon Etanercept + methotrexate + prednisone Improvement – the patient discontinued methotrexate Etanercept + prednisone Inadequately effective Etanercept + prednisone + Leflunomide Inadequately effective Adalimumab + prednisone + leflunomide Inadequately effective Leflunomide + prednisone + rituximab: Course 1 in Leflunomide stopped in 2006. Good March 2006, Course 2 in July 2007, Course 3 in response to rituximab November 2008, and Course 4 in September 2010
Over the last 10 years, the introduction of biologic agents has radically transformed the prognosis of rheumatoid arthritis (RA) but only at the cost of an increase in infectious complications. Alveolar echinococcosis (AE) is a rare but life-threatening infection with the larval form of Echinococcus multilocularis, whose successful treatment requires an early diagnosis. The prevalence of AE is increasing as a result of increased penetration in and around urban areas of foxes, which are hosts for the adult parasite [1,2]. We report a case of AE in a woman given rituximab therapy (Mabthera® ) to treat RA. To our knowledge, this is the first such case. This 59-year-old woman was diagnosed in 1996 with destructive RA. Her tests were positive for rheumatoid factors and negative for anti-citrullinated peptide antibodies (ACPAs). She received low-dose glucocorticoid therapy combined with several synthetic disease-modifying antirheumatic drugs, followed by several biological agents (Table 1). Finally, she was started on rituximab therapy. She presented with a dry cough, a gradual decline in general health, cholestasis, and positive acute-phase reactants. Her body temperature was normal. She reported eating wild berries since childhood. Thoracoabdominal and pelvic computed tomography visualized several multilobulated calcified lesions in the liver sug-
gesting AE (Fig. 1). However, serological tests were negative and a liver biopsy showed necrosis and a granulomatous response with no germinal layer. Investigations were negative for differential diagnoses. A treatment trial with doxycycline and albendazole was started. The abnormal liver images and cholestasis persisted. A second liver biopsy recovered a tumor-like lesion that was completely necrotic but contained laminated layer fragments, confirming the diagnosis of parasitic infection. The absence of a germinal layer and of scolices suggested AE rather than hydatid cyst. Excision surgery with continued albendazole therapy was performed. The histological results confirmed the diagnosis of AE. This case report illustrates the diagnostic challenges that occur in immunocompromised patients. Thus, the serological tests were negative in our patient and the first liver biopsy was inconclusive. Immunodepression may not only increase the frequency of AE, but also accelerate the development of the disease [3]. That immunosuppressive agents may allow accelerated parasite growth has been suggested on many occasions [4–6]. In our patient, the anti-B-cell agent rituximab may have promoted the development of AE. However, cell-mediated immunity seems to play the preponderant role in controlling AE, as opposed to humoral immunity [7,8]. Although the first manifestations of AE occurred after the introduction of rituximab in our patient, she had a long history of glucocorticoid therapy (albeit in low dosages) and of TNF␣ antagonist therapy. A role for these two treatments cannot be excluded, although few data are available on this point [9]. Conceivably, the larvae may have remained quiescent for several years before being reactivated by the rituximab infusions. Both RA itself [10,11] and all the available biological agents [12] increase the risk of bacterial and viral infections. Whether rituximab increases the risk of parasitic infections remains to be determined. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments
Fig. 1. Computed tomography in a 59-year-old patient, transverse section of the abdomen: cystic lesions in segment VII (white arrow) suggesting alveolar echinococcosis. No other lesions are visible.
We thank Prof. Hervé Pelloux and Dr Claudine Pinel for critical revision of the manuscript. We are grateful to Dr Laure Felix for a careful review of the images.
Letters to the editor / Joint Bone Spine 79 (2012) 323–334
References [1] McManus DP, Zhang W, Li J, et al. Echinococcosis. Lancet 2003;362: 1295–304. [2] Bresson-Hadni S, Piarroux R, Bartholomot B, et al. Echinococcose alvéolaire. EMC Hepatogastroenterologie 2005;2:86–104. [3] Gruener B, Cretu CM, Brunetti E, et al. Accelerated larval growth of Echinococcus spp. in the immunodeficient host? (abstract). Am J Trop Med Hyg 2008;6: 118. [4] Colebrook AL, Jenkins DD, Lightowlers MW. Antiparasitic effect of cyclosporine A on Echinococcus granulosus and characterization of the associated cyclophilin protein. Parasitology 2002;125:485–93. [5] Gottstein B, Hemphill A. Echinococcus multilocularis: The parasite-host interplay. Exp Parasitol 2008;119:447–52. [6] Magy N, Bresson-Hadni S, Augé B, et al. Une polyarthrite accompagnée, ou la cerise sur le gâteau. . .. Rev Med Interne 2000;21:460–1. [7] Hubner MP, Manfras BJ, Margos MC, et al. Echinococcus multilocularis metacestodes modulate cellular cytokine and chemokine release by peripheral blood mononuclear cells in alveolar echinococcosis patients. Clin Exp Immunol 2006;145:243–51. [8] Kocherscheidt L, Flakowski AK, Grüner B, et al. Echinococcus multilocularis: inflammatory and regulatory chemokine responses in patients with progressive, stable and cured alveolar echinococcosis. Exp Parasitol 2008;119: 467–74. [9] Weiner SM, Krenn V, Koelbel C, et al. Echinococcus multilocularis infection and TNF inhibitor treatment in a patient with rheumatoid arthritis. Rheumatol 2011;31:1399–400. [10] Franklin J, Lunt M, Bunn D, et al. Risk and predictors of infection leading to hospitalisation in a large primary-care-derived cohort of patients with inflammatory polyarthritis. Ann Rheum Dis 2006–2007;66: 308–12. [11] Smitten AL, Choi HK, Hochberg MC. The risk of hospitalized infection in patients with rheumatoid arthritis. Rheumatol 2008;35:387–93. [12] Raychaudhuri SP, Nguyen CT, Raychaudhuri SK, et al. Incidence and nature of infectious disease in patients treated with anti-TNF agents. Autoimmun Rev 2009;2:67–81.
Charlotte Dentan ∗ Roseline Mazet Mélanie Gilson Sylvie Marchou-Lopez Philippe Gaudin Service de rhumatologie, CHU Grenoble–Hôpital-Sud, avenue de Kimberley, BP 338, 38434 Echirolles cedex, France ∗ Corresponding author. E-mail address: [email protected] (C. Dentan)
3 October 2011 Available online 11 December 2011 doi:10.1016/j.jbspin.2011.10.014
Spondylarthritis and monoclonal gammopathy
a r t i c l e
i n f o
Keywords: Spondylarthritis Monoclonal gammopathy Myeloma Monoclonal gammopathy of undetermined significance
327
In ankylosing spondylitis (AS), evidence of B-cell activation includes IgA elevation during periods of disease activity [1] and B-cell infiltrates within the facet joints [2] and/or synovial membrane [3]. A role for IL-6 has been suggested in this B-cell activation [4,5]. However, few cases of monoclonal gammopathy have been reported in patients with AS. We conducted a retrospective multicenter study of 10 cases of AS with monoclonal gammopathy (Table 1). The diagnosis of AS antedated the diagnosis of monoclonal gammopathy in seven patients, by 1 to 31 years. In one patient, both diagnoses were made at the same time and in the remaining two patients, the AS was discovered during a workup for monoclonal gammopathy. The symptoms were predominantly axial and met modified New York criteria in eight patients. Peripheral involvement was noted in 3 patients and extraarticular manifestations in three patients (one case each of uveitis, Crohn’s disease, and psoriasis). The HLA-B27 antigen was found in four of nine patients. Disease activity was severe in five patients, and five patients required biological therapy. Of eight patients in whom monoclonal gammopathy was an incidental finding during follow-up for AS, seven had monoclonal gammopathy of undetermined significance (MGUS) and one had stage one monoclonal gammopathy. The remaining two patients had stage 3 multiple myeloma with bone pain as the presenting symptom; in both patients, the diagnosis of AS was made during the workup for myeloma. The monoclonal component isotype was IgG kappa in five patients, IgM lambda in three patients, IgG lambda in one patient, and IgA in one patient. In the seven patients with MGUS, the abnormality remained stable without treatment after 2 to 5 years of follow-up. In the two patients with stage 3 myeloma, chemotherapy was given, as well as a bone marrow transplant in one case; both patients died, after 4 and 5 years, respectively. Of the patients without myeloma, five (four with MGUS and one with stage 1 disease) received TNF␣ antagonist therapy for the AS, with no ill effects on the monoclonal gammopathy. We found a number of differences between our case-series and 72 previously reported cases [6–10] (Table 2). The association between AS and monoclonal gammopathy may appear to be fortuitous. However, in US veterans with AS, the relative risk of myeloma was 2.29 (95% confidence interval [95% CI], 1.55–3.40) and the relative risk of MGUS was 2.02 (95% CI, 1.14–3.56). The available follow-up data indicate that MGUS in patients with AS remains stable over time. More specifically, TNF␣ antagonist therapy in five patients from our case-series had no effect on the monoclonal gammopathy after 2 years above to 5 years of follow-up. No specific features of AS in patients with monoclonal gammopathy have been reported. In particular, monoclonal gammopathy does not seem associated with higher prevalences of peripheral involvement or extraarticular manifestations (30%) compared to other patients with AS. The lower prevalence of HLAB27 found in our case-series (45%) is consistent with an earlier study (40%) [6]. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
325
Table 1 Basic PDUS findings at all the entheseal sites examined in PsA and RA patients: prevalence, percentage (%) and grade (mean ± 95% CI). Prevalence and percentage (%) of basic PDUS findings Basic PDUS findings
PsA
RA
Hypoechogenicity Thickening Calcifications Enthesophytes Erosions Bony irregularity PD signal enthesis PD signal tendon Bursitis Tendon lesion
178 (16.7%) 72 (6.8%) 202 (19%) 391 (36.8%) 67 (6.3%) 126 (11.8%) 49 (4.6%) 64 (6%) 86 (8.1%) 5 (0.5%)
14 (3.8%) 19 (5.2%) 31 (8.5%) 107 (29.4%) 5 (1.4%) 53 (14.6%) 4 (1.1%) 12 (3.2%) 27 (7.4%) 1 (0.3%)
Grade of basic PDUS findings (mean ± 95%CI)
P
PsA 0.0000001 n.s 0.000003 0.011 0.0002 n.s 0.002 0.046 n.s n.s
0.2 0.1 0.3 0.5 0.08 0.12 0.07 0.1 0.01 0.04
P
RA ± ± ± ± ± ± ± ± ± ±
0.02 0.01 0.04 0.04 0.02 0.01 0.02 0.02 0.02 0.03
0.04 0.05 0.1 0.4 0.01 0.15 0.01 0.03 0.08 0.027
± ± ± ± ± ± ± ± ± ±
0.02 0.02 0.04 0.08 0.01 0.03 0.01 0.2 0.03 0.005
0.0001 n.s 0.0001 n.s 0.0001 n.s 0.002 0.009 n.s n.s
PDUS: power Doppler ultrasound; PsA: psoriatic arthritis; RA: rheumatoid arthritis; CI: confidence interval; PD: power Doppler.
2. Results One thousand and sixty-four entheses of 76 PsA patients and 224 of 26 RA controls were examined. The global number of entheses with PDUS-detected abnormalities (Fig. 1) were 756 in PsA patients and 224 in controls (P = 0.0008). At enthesis level, the prevalence and grade of most inflammatory and structural damage lesions (Table 1) resulted to be significantly higher in PsA than in RA (P < 0.0000001 and 0.01 respectively). The global entheseal PDUS score showed a more serious involvement in PsA than in controls (22.77 ± 18.8 vs 14.04 ± 9.8; P = 0.03). Poor significant correlations were demonstrated between global entheseal PDUS score and MASES (P < 0.033). The analysis of the findings at patient level didn’t give results able to discriminate between RA and PsA patients.
[8] Jacobs JC. Spondylarthropathy and enthesopathy. Arch Intern Med 1983;143:103–7. [9] McGonagle D, Gibbon W, Emery P. Classification of inflammatory arthritis by enthesitis. Lancet 1998;352:1137–40.
Annamaria Iagnocco a,∗ Antonio Spadaro a Antonio Marchesoni b Alberto Cauli c Orazio De Lucia b Alessandra Gabba c Silvia Takanen a Monica Montepaone a Fabio Massimo Perrotta a Maria Antonietta D’Agostino d Alessandro Mathieu c Guido Valesini a a Rheumatology Unit, Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, Policlinico Umberto 1◦ , Viale del Policlinico 155, 00161 Rome, Italy b Rheumatology Department, Istituto Ortopedico Gaetano Pini, Milano, Italy c Rheumatology Department, Università di Cagliari, Cagliari, Italy d Department of Rheumatology, université Paris Ouest-Versailles-Saint-Quentin-en-Yvelines, hôpital Ambroise-Paré, AP–HP, 92100 Paris, France
3. Discussion This is the first study showing PDUS findings indicative of extensive and severe entheseal abnormalities, related both to inflammation and structural damage, in PsA. Enthesitis, a typical pathological feature of SpA, may assume variable aspects and different locations [7–9]. However, due to the low sensitivity of clinical assessment in the detection of inflammatory musculoskeletal changes, peripheral enthesitis is frequently mixed up with other joint and soft tissues disorders by physical examination and its presence may be often underestimated [1]. Therefore, imaging modalities, such as musculoskeletal US, play a fundamental role in this field helping in the detection of various entheseal abnormalities at different entheseal sites.
∗ Corresponding
author. Tel.: +39 06 49974637; fax: +39 06 49974642. E-mail address: [email protected] (A. Iagnocco)
Disclosure of interest
2 October 2011 Available online 26 November 2011
The authors declare that they have no conflicts of interest concerning this article. doi:10.1016/j.jbspin.2011.10.005
References [1] D’Agostino MA, Said-Nahal R, Hacquard-Bouder C, et al. Assessment of peripheral enthesitis in the spondylarthropathies by ultrasonography combined with power Doppler: a cross-sectional study. Arthritis Rheum 2003;48:523–33. [2] Riente L, Delle Sedie A, Filippucci E, et al. Ultrasound imaging for the rheumatologist IX. Ultrasound imaging in spondyloarthritis. Clin Exp Rheumatol 2007;25:349–53. [3] Filippucci E, Aydin SZ, Karadag O, et al. Reliability of high-resolution ultrasonography in the assessment of Achilles tendon enthesopathy in seronegative spondyloarthropathies. Ann Rheum Dis 2009;68:1850–5. [4] Balint PV, Kane D, Wilson H, et al. Ultrasonography of entheseal insertions in the lower limb in spondyloarthropathy. Ann Rheum Dis 2002;61:905–10. ˜ [5] De Miguel E, Cobo T, Munoz-Fernández S, et al. Validity of enthesis ultrasound assessment in spondylarthropathy. Ann Rheum Dis 2009;68:169–74. [6] Wakefield RJ, D’Agostino MA, Iagnocco A, et al. The OMERACT Ultrasound Group: status of current activities and research directions. J Rheumatol 2007;34:848–51. [7] McGonagle D, Khan MA, Marzo-Ortega H, et al. Enthesitis in spondylarthropathy. Curr Opin Rheumatol 1999;11:244–50.
Rheumatoid arthritis, alveolar echinococcosis, and rituximab: A case report夽
a r t i c l e
i n f o
Keywords: Alveolar echinococcosis Rituximab Rheumatoid arthritis
夽 The first two authors contributed equally to this manuscript.
326
Letters to the editor / Joint Bone Spine 79 (2012) 323–334
Table 1 Medications taken to treat rheumatoid arthritis and reasons for changes. Medication history Start date
End date
Medications
May 1996 June 1996 November 1996 June 1997 January 1998
May 1996 June 1996 October 1996 April 1997 January 1998 November 1998
Indomethacin Prednisone Penicillamine up to 900 mg/day + prednisone Methotrexate + prednisone Penicillamine + prednisone Aurothiopropanolsulfonate + prednisone
Reason for stopping
January 1999 May 1999 March 2001 May 2001 October 2002
May 1999 March 2001 April 2001 October 2002 October 2003
October 2003 July 2004 November 2005 March 2006
July 2004 November 2005 February 2006
Inadequately effective Inadequately effective Effective but proteinuria 1.17 g/24 h Inadequately effective Proteinuria starting at 900 mg/day Inadequately effective and adverse effects Methotrexate + prednisone + hydroxychloroquine Escape phenomenon Methotrexate + prednisone + hydroxychloroquine + sulfasalazine Inadequately effective Methotrexate + prednisone Not effective Methotrexate + prednisone + infliximab Escape phenomenon Etanercept + methotrexate + prednisone Improvement – the patient discontinued methotrexate Etanercept + prednisone Inadequately effective Etanercept + prednisone + Leflunomide Inadequately effective Adalimumab + prednisone + leflunomide Inadequately effective Leflunomide + prednisone + rituximab: Course 1 in Leflunomide stopped in 2006. Good March 2006, Course 2 in July 2007, Course 3 in response to rituximab November 2008, and Course 4 in September 2010
Over the last 10 years, the introduction of biologic agents has radically transformed the prognosis of rheumatoid arthritis (RA) but only at the cost of an increase in infectious complications. Alveolar echinococcosis (AE) is a rare but life-threatening infection with the larval form of Echinococcus multilocularis, whose successful treatment requires an early diagnosis. The prevalence of AE is increasing as a result of increased penetration in and around urban areas of foxes, which are hosts for the adult parasite [1,2]. We report a case of AE in a woman given rituximab therapy (Mabthera® ) to treat RA. To our knowledge, this is the first such case. This 59-year-old woman was diagnosed in 1996 with destructive RA. Her tests were positive for rheumatoid factors and negative for anti-citrullinated peptide antibodies (ACPAs). She received low-dose glucocorticoid therapy combined with several synthetic disease-modifying antirheumatic drugs, followed by several biological agents (Table 1). Finally, she was started on rituximab therapy. She presented with a dry cough, a gradual decline in general health, cholestasis, and positive acute-phase reactants. Her body temperature was normal. She reported eating wild berries since childhood. Thoracoabdominal and pelvic computed tomography visualized several multilobulated calcified lesions in the liver sug-
gesting AE (Fig. 1). However, serological tests were negative and a liver biopsy showed necrosis and a granulomatous response with no germinal layer. Investigations were negative for differential diagnoses. A treatment trial with doxycycline and albendazole was started. The abnormal liver images and cholestasis persisted. A second liver biopsy recovered a tumor-like lesion that was completely necrotic but contained laminated layer fragments, confirming the diagnosis of parasitic infection. The absence of a germinal layer and of scolices suggested AE rather than hydatid cyst. Excision surgery with continued albendazole therapy was performed. The histological results confirmed the diagnosis of AE. This case report illustrates the diagnostic challenges that occur in immunocompromised patients. Thus, the serological tests were negative in our patient and the first liver biopsy was inconclusive. Immunodepression may not only increase the frequency of AE, but also accelerate the development of the disease [3]. That immunosuppressive agents may allow accelerated parasite growth has been suggested on many occasions [4–6]. In our patient, the anti-B-cell agent rituximab may have promoted the development of AE. However, cell-mediated immunity seems to play the preponderant role in controlling AE, as opposed to humoral immunity [7,8]. Although the first manifestations of AE occurred after the introduction of rituximab in our patient, she had a long history of glucocorticoid therapy (albeit in low dosages) and of TNF␣ antagonist therapy. A role for these two treatments cannot be excluded, although few data are available on this point [9]. Conceivably, the larvae may have remained quiescent for several years before being reactivated by the rituximab infusions. Both RA itself [10,11] and all the available biological agents [12] increase the risk of bacterial and viral infections. Whether rituximab increases the risk of parasitic infections remains to be determined. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. Acknowledgments
Fig. 1. Computed tomography in a 59-year-old patient, transverse section of the abdomen: cystic lesions in segment VII (white arrow) suggesting alveolar echinococcosis. No other lesions are visible.
We thank Prof. Hervé Pelloux and Dr Claudine Pinel for critical revision of the manuscript. We are grateful to Dr Laure Felix for a careful review of the images.
Letters to the editor / Joint Bone Spine 79 (2012) 323–334
References [1] McManus DP, Zhang W, Li J, et al. Echinococcosis. Lancet 2003;362: 1295–304. [2] Bresson-Hadni S, Piarroux R, Bartholomot B, et al. Echinococcose alvéolaire. EMC Hepatogastroenterologie 2005;2:86–104. [3] Gruener B, Cretu CM, Brunetti E, et al. Accelerated larval growth of Echinococcus spp. in the immunodeficient host? (abstract). Am J Trop Med Hyg 2008;6: 118. [4] Colebrook AL, Jenkins DD, Lightowlers MW. Antiparasitic effect of cyclosporine A on Echinococcus granulosus and characterization of the associated cyclophilin protein. Parasitology 2002;125:485–93. [5] Gottstein B, Hemphill A. Echinococcus multilocularis: The parasite-host interplay. Exp Parasitol 2008;119:447–52. [6] Magy N, Bresson-Hadni S, Augé B, et al. Une polyarthrite accompagnée, ou la cerise sur le gâteau. . .. Rev Med Interne 2000;21:460–1. [7] Hubner MP, Manfras BJ, Margos MC, et al. Echinococcus multilocularis metacestodes modulate cellular cytokine and chemokine release by peripheral blood mononuclear cells in alveolar echinococcosis patients. Clin Exp Immunol 2006;145:243–51. [8] Kocherscheidt L, Flakowski AK, Grüner B, et al. Echinococcus multilocularis: inflammatory and regulatory chemokine responses in patients with progressive, stable and cured alveolar echinococcosis. Exp Parasitol 2008;119: 467–74. [9] Weiner SM, Krenn V, Koelbel C, et al. Echinococcus multilocularis infection and TNF inhibitor treatment in a patient with rheumatoid arthritis. Rheumatol 2011;31:1399–400. [10] Franklin J, Lunt M, Bunn D, et al. Risk and predictors of infection leading to hospitalisation in a large primary-care-derived cohort of patients with inflammatory polyarthritis. Ann Rheum Dis 2006–2007;66: 308–12. [11] Smitten AL, Choi HK, Hochberg MC. The risk of hospitalized infection in patients with rheumatoid arthritis. Rheumatol 2008;35:387–93. [12] Raychaudhuri SP, Nguyen CT, Raychaudhuri SK, et al. Incidence and nature of infectious disease in patients treated with anti-TNF agents. Autoimmun Rev 2009;2:67–81.
Charlotte Dentan ∗ Roseline Mazet Mélanie Gilson Sylvie Marchou-Lopez Philippe Gaudin Service de rhumatologie, CHU Grenoble–Hôpital-Sud, avenue de Kimberley, BP 338, 38434 Echirolles cedex, France ∗ Corresponding author. E-mail address: [email protected] (C. Dentan)
3 October 2011 Available online 11 December 2011 doi:10.1016/j.jbspin.2011.10.014
Spondylarthritis and monoclonal gammopathy
a r t i c l e
i n f o
Keywords: Spondylarthritis Monoclonal gammopathy Myeloma Monoclonal gammopathy of undetermined significance
327
In ankylosing spondylitis (AS), evidence of B-cell activation includes IgA elevation during periods of disease activity [1] and B-cell infiltrates within the facet joints [2] and/or synovial membrane [3]. A role for IL-6 has been suggested in this B-cell activation [4,5]. However, few cases of monoclonal gammopathy have been reported in patients with AS. We conducted a retrospective multicenter study of 10 cases of AS with monoclonal gammopathy (Table 1). The diagnosis of AS antedated the diagnosis of monoclonal gammopathy in seven patients, by 1 to 31 years. In one patient, both diagnoses were made at the same time and in the remaining two patients, the AS was discovered during a workup for monoclonal gammopathy. The symptoms were predominantly axial and met modified New York criteria in eight patients. Peripheral involvement was noted in 3 patients and extraarticular manifestations in three patients (one case each of uveitis, Crohn’s disease, and psoriasis). The HLA-B27 antigen was found in four of nine patients. Disease activity was severe in five patients, and five patients required biological therapy. Of eight patients in whom monoclonal gammopathy was an incidental finding during follow-up for AS, seven had monoclonal gammopathy of undetermined significance (MGUS) and one had stage one monoclonal gammopathy. The remaining two patients had stage 3 multiple myeloma with bone pain as the presenting symptom; in both patients, the diagnosis of AS was made during the workup for myeloma. The monoclonal component isotype was IgG kappa in five patients, IgM lambda in three patients, IgG lambda in one patient, and IgA in one patient. In the seven patients with MGUS, the abnormality remained stable without treatment after 2 to 5 years of follow-up. In the two patients with stage 3 myeloma, chemotherapy was given, as well as a bone marrow transplant in one case; both patients died, after 4 and 5 years, respectively. Of the patients without myeloma, five (four with MGUS and one with stage 1 disease) received TNF␣ antagonist therapy for the AS, with no ill effects on the monoclonal gammopathy. We found a number of differences between our case-series and 72 previously reported cases [6–10] (Table 2). The association between AS and monoclonal gammopathy may appear to be fortuitous. However, in US veterans with AS, the relative risk of myeloma was 2.29 (95% confidence interval [95% CI], 1.55–3.40) and the relative risk of MGUS was 2.02 (95% CI, 1.14–3.56). The available follow-up data indicate that MGUS in patients with AS remains stable over time. More specifically, TNF␣ antagonist therapy in five patients from our case-series had no effect on the monoclonal gammopathy after 2 years above to 5 years of follow-up. No specific features of AS in patients with monoclonal gammopathy have been reported. In particular, monoclonal gammopathy does not seem associated with higher prevalences of peripheral involvement or extraarticular manifestations (30%) compared to other patients with AS. The lower prevalence of HLAB27 found in our case-series (45%) is consistent with an earlier study (40%) [6]. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.