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Amyloidosis complicating spondyloarthropathies: Study of 15 cases
Med Clin (Barc). 2015;145(8):327–331
www.elsevier.es/medicinaclinica
Original article
Amyloidosis complicating spondyloarthropathies: Study of 15 cases夽 Samantha Rodríguez-Muguruza a,∗ , Melania Martínez-Morillo a , Susana Holgado a , Xavier Saenz-Sarda b , Lourdes Mateo a , Xavier Tena a , Alejandro Olivé a a b
Servicio de Reumatología, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain Servicio de Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 8 April 2014 Accepted 19 June 2014 Available online 16 March 2016 Keywords: Secondary amyloidosis Spondyloarthropathy Renal failure
a b s t r a c t Background and objective: Secondary amyloidosis (AA) is a rare complication of rheumatic diseases. Objective: The aim of this study was to determine the frequency of symptomatic amyloidosis AA in patients with spondyloarthropathy. Patients and method: Retrospective study (1984–2013). We reviewed the medical records of patients with spondyloarthropathy who had a histological diagnosis of amyloidosis AA (15 patients). Results: We identified 1.125 patients with spondyloarthropathies. Fifteen (1.3%) patients with amyloidosis AA were recruited. It was suspected in 14 patients (93.3%) because of nephrotic syndrome in most of them: 14 were symptomatic (93.3%): 5 (33.3%) ankylosing spondylitis (AS), 5 (33.3%) spondylitis associated with inflammatory bowel diseases (IBD), 4 (26.7%) psoriatic arthritis, and one (6.7%) reactive arthritis. The mean disease duration was 23.9 years. Mortality after one and 5 years of follow-up was 30 and 50% respectively. Conclusions: The frequency of clinical amyloidosis AA in our patients was 1.3%. There was a marked male predominance, with AS or IBD. Clinical amyloidosis was diagnosed at a relatively late stage in spondyloarthropathy. ˜ S.L.U. All rights reserved. © 2014 Elsevier Espana,
Amiloidosis secundaria a espondiloartritis: estudio de 15 casos r e s u m e n Palabras clave: Amiloidosis secundaria Espondiloartritis Insuficiencia renal
Fundamento y objetivo: La amiloidosis secundaria (AA) es una complicación de enfermedades inflamatorias crónicas tales como las enfermedades reumáticas. El objetivo de este estudio fue evaluar la prevalencia de amiloidosis AA en una serie retrospectiva de pacientes con espondiloartritis. Pacientes y método: Estudio retrospectivo entre 1984-2013. Se revisaron las historias clínicas de los pacientes con diagnóstico de espondiloartritis y amiloidosis AA. Resultados: Se identificaron 1.125 pacientes con espondiloartritis. Quince (1,3%) presentaban amiloidosis AA: 14 (93,3%) fueron sintomáticos, en la mayoría de ellos se presentó como síndrome nefrótico. Cinco (33,3%) estaban diagnosticados de espondilitis anquilosante (EA), 5 (33,3%) de espondiloartritis asociada a enfermedad inflamatoria intestinal (EII), 4 (26,7%) de artritis psoriásica y uno (6,7%) de artritis reactiva. La media de edad de evolución desde el diagnóstico de espondiloartritis hasta el diagnóstico de amiloidosis ˜ ˜ y a los 5 anos ˜ fue del 30 y 50%, respectivamente. AA fue de 23,9 anos. La mortalidad al ano Conclusiones: En este estudio retrospectivo de pacientes con espondiloartritis, la prevalencia de amiloidosis AA sintomática fue del 1,24%. La mayoría fueron varones con una EA o espondiloartritis asociada a EII de larga evolución. El motivo más frecuente de sospecha del desarrollo de amiloidosis AA fue el síndrome nefrótico. ˜ S.L.U. Todos los derechos reservados. © 2014 Elsevier Espana,
夽 Please cite this article as: Rodríguez-Muguruza S, Martínez-Morillo M, Holgado S, Saenz-Sarda X, Mateo L, Tena X, et al. Amiloidosis secundaria a espondiloartritis: estudio de 15 casos. Med Clin (Barc). 2015;145:327–331. ∗ Corresponding author. E-mail address: [email protected] (S. Rodríguez-Muguruza). ˜ S.L.U. All rights reserved. 2387-0206/© 2014 Elsevier Espana,
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S. Rodríguez-Muguruza et al. / Med Clin (Barc). 2015;145(8):327–331
Introduction Amyloidosis is a disease characterized by the extracellular deposition of a set of fibrillar proteins that have a common characteristic: they adopt a ß pleated sheet structure. There are 2 types, primary amyloidosis, mainly consisting of fragments of light immunoglobulin chains, and secondary amyloidosis (AA), consisting of protein A fibrils.1 AA amyloidosis is a complication of chronic inflammatory diseases whose diagnosis can be performed in the subclinical phase (incidentally as pathological finding), or the symptomatic phase, in which its manifestations vary according to the affected organ. An estimated 13% of patients with rheumatoid arthritis develop this complication throughout its progression, symptomatically,2 and up to 29% subclinically.3 Spondyloarthritis prevalence is lower and therefore not so well described; it is estimated that ankylosing spondylitis (AS) represents 1.1% in its symptomatic form4 and 7%5 in its asymptomatic manifestation. In the absence of comparative studies on the incidence of AA amyloidosis in different spondyloarthritis, and since a diagnostic coding system has only been available for 29 years, it was proposed to describe the clinical and laboratory characteristics, as well as the treatment received in a series of 15 patients with spondyloarthritis and AA amyloidosis diagnosed at a university reference site.
Patients and method Databases of the Rheumatology (CIPPER) and Pathology Departments of the Germans Trias i Pujol University Hospital, with a reference population of 850,000 inhabitants, were retrospectively reviewed (1984–2013). During this period, 1125 patients with spondyloarthritis were identified, all of them diagnosed according to current criteria. Patients treated in district hospitals within our area of reference with Rheumatology departments were not included in the study population. The diagnosis of AA amyloidosis was made by visualizing amyloid deposits under polarized light, characterized by its apple green with Congo red staining; likewise, immunochemistry was performed to confirm the subtype. Both, paper and electronic medical records of all patients were reviewed retrospectively. The following variables were collected: epidemiological data, clinical manifestations, treatment received, laboratory tests such as complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) (by nephelometry) and creatinine, area of diagnostic biopsy, treatment and progression. Patients with other entities that may be associated with AA amyloidosis, such as chronic infections or malignancies, at the time of diagnosis and during the course, were excluded.
Between 1985 and 1989, 3 patients were diagnosed with AA amyloidosis, 8 between 1990 and 1999, 3 between 2000 and 2010, and 1 patient in 2010. The average age at diagnosis for spondyloarthritis was 35.13 years (range 22–59), and 57.7 years (range 33–76) for AA amyloidosis. The average age of disease progression until the diagnosis of amyloidosis was 23.9 years (range 4–49). Ten patients (66.7%) had axial involvement, and 12 (80%), peripheral. Of the 12 patients who had genetic testing available, 6 (50%) were positive to B27 histocompatibility antigen (HLA-B27). The signs that made suspect the presence of AA amyloidosis in the 14 symptomatic patients (93.3%) were: nephrotic syndrome in 4 (28.6%), acute renal failure in 3 (21.4%), non-nephrotic range proteinuria in 3 (21.4%), chronic renal failure in 2 (14.3%), diarrhoea in one (7.1%) and haematuria in another (7.1%). In an asymptomatic patient the diagnosis was made incidentally while analysing the gallbladder after a cholecystectomy by gallstones; this patient had symptoms 1.5 years after the incidental diagnosis. The location of the AA amyloidosis’ diagnostic biopsy was: 6 in the rectal mucosa (40%), 4 in subcutaneous fat (26.7%), 3 renal (20%), 1 in the bladder (6.7%) and 1 in the gallbladder (6.7%). Three subcutaneous fat biopsies showed a false negative result. The diagnosis was confirmed by renal (2 patients) and rectal (1 patient) biopsy. The mean values of ESR and CRP before diagnosis of amyloidosis during the first hour were 65.4 mm and 25.22 mm mg/l, respectively. Serum creatinine values ranged between 0.8 and 3.2 mg/dl at the time of AA amyloidosis diagnosis and the last determination had variations between 1 and 4 mg/dl, regardless of dialysis status. Ten patients (66.7%) received chlorambucil and/or colchicine as a treatment for AA amyloidosis, with poor subsequent progression. Nine died, 2 from chronic renal failure and 7 from multiple organ failure secondary to sepsis. Five patients (33.3%) were treated with anti-tumour necrosis factor (TNF) ␣; infliximab was used in all. AA amyloidosis was the indication in 4 cases. Despite treatment with anti-TNF-␣, 2 patients required haemodialysis, both elderly at the time of AA amyloidosis diagnosis. The rest (60%) had an improvement in the figures of proteinuria and creatinine with respect to the time of diagnosis. One patient (20%) died of multiple organ failure secondary to pulmonary sepsis. During progression, 6 patients (40%) had end-stage renal failure requiring haemodialysis. Ten patients (66.7%) died: 2 due to causes secondary to renal failure and 8 due to multiple organ failure secondary to sepsis. Mortality was 30 and 50% at one and five years, respectively, for AA amyloidosis diagnosis.
Discussion Results During this period, 1125 patients with spondyloarthritis were visited at the Rheumatology Department, as follows: psoriatic arthritis 509 (45%), AS 263 (23%), spondyloarthritis associated with inflammatory bowel disease (IBD) 128 (11.3%), undifferentiated spondyloarthritis 190 (16.8%) and reactive arthritis 35 (3%). Of these, 41% were female and 59% male. Fifteen patients (1.3%) developed AA amyloidosis: 11 males (73.3%) and 4 women (26.7%). The type of Spondyloarthritis manifested was: 5 AS (33.3%), 5 spondyloarthritis associated with IBD (33.3%), 4 psoriatic arthritis (26.7%) and reactive arthritis (6.7%). The clinical and laboratory characteristics of the patients are summarized in Tables 1 and 2.
AA amyloidosis is a rare entity in spondyloarthritis. Its low incidence explains the limited number of patients obtained in a single hospital over a period of 29 years. A 1.1% incidence of symptomatic AA amyloidosis has been reported in AS patients,3 which correlates with the findings in this series (1.9%). Gratacos et al. describe that the subclinical form is present in 7% of patients.5,6 In this series, these data is not available, since clinical practice does not include biopsies of abdominal fat in asymptomatic patients. None of our cases of AA amyloidosis associated with AS was diagnosed incidentally. In 1998 Kagan et al. reported 39 cases of symptomatic AA amyloidosis in patients with psoriasis, 85% of them with associated arthropathy.5 Its actual incidence is not well documented, only a
Table 1 Clinical and analytical characteristics of 15 patients with spondyloarthropathy and secondary amyloidosis. 22/M
40/M
29/F
59/F
25/M
38/M
28/M
30M
Diagnosis
Psoriatic arthritis
Axial involvement Peripheral involvement HLA-B27 Anti-TNF treatment/indication Disease duration (years) Amyloid diagnosis age (years) ESR at diagnosis (mm) CRP at diagnosis (mg/dl) Biopsy location
Yes Polyarticular Positive Infliximab/arthritis 49 71 70 87 Gallbladder
Psoriatic arthritis No Oligoarticular NA No 28 68 27 3.8 Bladder
Psoriatic arthritis No Polyarticular Positive Infliximab/AA 4 33 125 80 Kidney
Ankylosing spondylitis Yes No NA No 37 62 NA NA Rectum
Ankylosing spondylitis Yes Polyarticular Positive No 6 44 NA NA Rectum
Ankylosing spondylitis Yes Polyarticular Positive Infliximab/AA 36 64 50 17.5 Rectum
Ankylosing spondylitis Yes Polyarticular Negative No 39 69 80 3.8 Rectum
Biopsy indication
Cholecystectomy
Haematuria Yes Yes/sepsis 1.2 1.9
Chronic renal failure No No 2.2 1.8
Proteinuria
Yes Yes/sepsis 1 5
Acute renal failure No Yes/sepsis 3 3.3
Diarrhoea
Dialysis Death/motive Creatinine at diagnosis Last creatinine
Nephrotic syndrome No No 1.1 1
Psoriatic arthritis No Yes Negative No 20 56 23 1.68 Subcutaneous fat Nephrotic syndrome No No 0.9 1
Yes Yes/sepsis NA 1.8
No Yes/CRF NA 3
AS onset age (years)/sex
24/M
40/M
40/F
30/M
44/M
41/M
37/F
Diagnosis
Ankylosing spondylitis Yes Polyarticular Positive No 21 45 50 6 Subcutaneous fat Acute renal failure No Yes/CRF 2.5 4
Spondyloarthropathy associated with IBD Yes No Negative Infliximab/AA 24 67 69 10.6 Kidney
Spondyloarthropathy associated with IBD Yes Polyarticular Negative No 20 60 82 14 Rectum
Spondyloarthropathy associated with IBD No Polyarticular Negative No 10 40 93 3.4 Rectum
Spondyloarthropathy associated with IBD Yes Polyarticular Positive Infliximab/AA 17 61 20 40 Kidney
Spondyloarthropathy associated with IBD Yes No Negative No 35 76 96 34.9 Subcutaneous fat
Acute renal failure
Nephrotic syndrome
Chronic renal failure
Nephrotic syndrome
Proteinuria
Reactive arthritis No Polyarticular NA No 13 50 NA NA Subcutaneous fat Proteinuria
Yes No 3.2 6
No Yes/sepsis 1.8 2.1
Yes Yes/sepsis 2.3 NA
No No 1.7 1.2
No Yes/sepsis 1.8 4.6
Yes Yes/sepsis NA NA
Axial involvement Peripheral involvement HLA-B27 Anti-TNF treatment/indication Disease duration (years) Amyloid diagnosis age (years) ESR at diagnosis (mm) CRP at diagnosis (mg/dl) Biopsy location Biopsy indication Dialysis Death/motive Creatinine at diagnosis Last creatinine
S. Rodríguez-Muguruza et al. / Med Clin (Barc). 2015;145(8):327–331
AS onset age (years)/sex
AS: spondyloarthropathy; F: female; HLA-B27: positive B27 histocompatibility antigen; ARF: acute renal failure; CRF: chronic renal failure; M: male; NA: not available; CRP: C-reactive protein; TNF: tumour necrosis factor; ESR: erythrocyte sedimentation rate.
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Table 2 Case selection algorithm. 1125 patients with spondyloarthritis
509 psoriatic arthritis (45%)
263 EA (23%)
128 spondylitis associated with IBD (11,5%)
3 AA amyloidosis symptomatic (0,6%)
5 AA amyloidosis symptomatic (1,9%)
5 AA amyloidosis symptomatic (3,9%)
190 spondyloarthritis 35 reactive arthritis undifferentiated (3%) (16,8%)
1 AA amyloidosis subclinical (2,8%)
+ 1 AA amyloidosis subclinical (0,2%)
AA: secondary; AS: ankylosing spondylitis; IBD: inflammatory bowel disease.
few isolated cases are available.6–12 There are no previous reports of subclinical AA amyloidosis in patients with psoriatic arthritis; in the present study, a patient is in this phase of the disease, with symptoms after 1.5 years of follow up. There are no previous communications in medical literature about reactive arthritis and AA amyloidosis. Table 3 describes the most relevant cases reported in the literature.4,13–16 In this case series, a marked predominance of males (73.3%) was evident, which is attributed to the increased frequency of spondyloarthritis and its greater aggressiveness in this sex. Symptomatic AA amyloidosis in AS usually occurs in patients with long-term disease, with significant axial and peripheral involvement as well as ESR and Bath Ankylosing Spondylitis Disease Activity Index greater at the beginning of the disease, and lower haemoglobin levels.6,17 Overall, the time of disease progression in our patients was over 10 years, similar to that found in previous series.4,6,7 However, one of our patients with psoriatic arthritis presented a symptomatic AA amyloidosis at 4 years of progression, possibly due to the aggressiveness of the disease, its mutilating character and a lack of appropriate therapeutic monitoring in the context of concomitant sociopathy. There is a clear association between HLA-B27 and spondyloarthritis. However, its frequency is different in each of them; in our cases, only 50% were positive. As numerous studies show, symptomatic AA amyloidosis occurs in a greater proportion of patients with peripheral joint involvement;5,6,17 in our case series,
80% had such involvement. As it is well known, forms of spondyloarthritis with peripheral involvement have less association with HLA-B27, which could explain the lower incidence of this genetic marker in our patients. The diagnosis of AA amyloidosis can be obtained by performing a biopsy of any organ; usually, with a preference for those in which there is suspicion of amyloid infiltration. In our case series, 40% of patients were diagnosed by performing rectal biopsy. Although a biopsy of subcutaneous fat is more accessible and less aggressive, in the past and according to protocol, our hospital used a rectal biopsy whenever there was suspicion of amyloidosis. A false negative was the result in 3 cases of abdominal fat biopsy. Although most clinical practice guidelines recommended an abdominal fat biopsy as first diagnostic test to screen for amyloidosis, its sensitivity varies greatly depending on the fat extraction technique and the sample processing. In this study, 2 of the 3 false positives were due to the sample being insufficient. Significantly, in this series, the mean age at diagnosis of AA amyloidosis was 57.7 years, higher than that found in previous series.4,13–16 A downward trend in the incidence of symptomatic AA amyloidosis over the years is observed in this study, possibly due to better control of the underlying disease with the use of anti-TNF-␣ treatment. The approach of AA amyloidosis in inflammatory arthropathy is based on treating the underlying disease. As regards spondyloarthritis, there are cases and small series showing that TNF-␣ antagonists improve clinical signs and symptoms and prevent renal function deterioration.4,6–13,16,18,19 In the present series, 5 patients required the use of anti-TNF-␣ and amyloidosis was the indication in 4 of them. The outcome was favourable in 60% of them, or similar decline in creatinine levels at diagnosis. The other 2 patients required haemodialysis possibly due to the long progression of the disease and advanced age at diagnosis. In the other patient, the lack of improvement despite treatment with anti-TNF-␣ could be due to the fact that AA amyloidosis onset was in the context of acute renal failure. The use of biological drugs could not be considered in the other 10 patients, as they were the oldest cases, prior to the availability of those drugs. Notably, there have been reports of improvement with colchicine and chlorambucil.6,19 AA amyloidosis has a high mortality due to end-stage renal disease, infectious processes and intestinal perforation or bleeding. Studies conducted prior to the availability of biologic drugs show that AA amyloidosis was the direct cause of death in 13% of patients with AS, and that it reduced the average life 2.37 years, with a 30% survival rate at 5 years.20,21
Table 3 Relevant cases of spondyloarthritis and secondary amyloidosis described in literature. Spondyloarthritis, n
AA amyloidosis, n
Age at diagnosis of AA amyloidosis, average in years
Progression time in years
Biopsy site
Symptoms
Treatment
Nephrotic syndrome and non-nephrotic proteinuria Subclinical Nephrotic and non-nephrotic proteinuria, ARF Subclinical
ND
Ben Taarit et al.13
AS/210
6
36.8
ND
Renal (5), labial (1)
Singh et al.14 Dönmez et al.4
AS/72 AS/730
5 8
39.2 48
15.2 18.6
Subcutaneous fat Rectal (3), renal (1)
Immonen et al.15
Psoriatic Arthritis/70
3
36
41.857
Fernandez-Nebro et al.16 Gratacos et al.6
Psoriatic arthritis/ND
4
52
16
Colon (1), intestine (1), ND (10) Renal
10
57
24.1
Subcutaneous fat
AS/137
AA: secondary; AS: ankylosing spondylitis; ARF: acute renal failure; ND: not determined.
ARF, proteinuria Subclinical
ND Infliximab, etanercept, adalimumab Tocilizumab Infliximab, etanercept ND
S. Rodríguez-Muguruza et al. / Med Clin (Barc). 2015;145(8):327–331
In the present series, AA amyloidosis was the direct cause of death in only 2 patients; the majority (8 cases) died from secondary infections. Although it is a study which includes a substantial number of patients with ankylosing spondyloarthritis and for a long period of time, this is limited by its retrospective nature and the relative small number of patients due to of the low incidence of this disease. In conclusion, AA amyloidosis should be suspected in patients with longstanding spondyloarthritis with persistently elevated acute phase reactants, proteinuria or renal failure. The treatment is controversial and is based on case reports and clinical experience; however, the role of anti-TNF-␣ is promising. Conflicts of interest The authors declare that they have no conflicts of interest. References 1. Maduell F, Calco C, Hernández-Jara J, García Pérez H, Torregosa E, Rius A. Secondary amyloidosis (AA) and renal disease. Nefrologia. 2003;23:321–6. 2. Mueller OS. Amyloidosis. Current rheumatology, diagnosis & treatment. 2nd ed. USA: McGraw Hill; 2007. 3. Wiland P, Wojtala R, Gooacre J, Szechinski J. The prevalence of subclinical amyloidosis in Polish patients with rheumatoid arthritis. Clin Rheumatol. 2004;23:193–8. 4. Dönmez S, Pamuk ÖN, Pamuk GE, Aydo˘gdu E, Inman R. Secondary amyloidosis in ankylosing spondylitis. Rheumatol Int. 2013;33:1725–9. 5. Kagan A, Husza’r M, Frumkin A, Rapoport J. Reversal of nephrotic syndrome due to AA amyloidosis in psoriatic patients on long-term colchicine treatment. Case report and review of the literature. Nephron. 1999;82:348–53. 6. Gratacos J, Orellana C, Sanmarti R, Sole M, Collado A, Gomez-Casanovas E, et al. Secondary amyloidosis in ankylosing spondylitis. A systematic survey of 137 patients using abdominal fat aspiration. J Rheumatol. 1997;24: 912–5.
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7. Bergis M, Dega H, Planquois V, Benichou O, Dubertret L. Amyloidosis complicating psoriatic arthritis. Ann Dermatol Venereol. 2003;130:1039–42 (French). 8. Qureshi MS, Sandle GI, Kelly JK, Fox H. Amyloidosis complicating psoriatic arthritis. Br Med J. 1977;2:302. 9. Lambert JR, Wright V. Eye inflammation in psoriatic arthritis. Ann Rheum Dis. 1976;35:354–6. 10. Pérez Silvestre J, Campos Fernández C, Baixauli Rubio A, Calvo Catalá J, GonzálezCruz MI, Herrera Ballester A. Psoriatic arthritis complicated with secondary amyloidosis. An Med Interna. 2008;25:247–9 [Spanish]. 11. Ryan JG, Dorman AM, O’Connell PG. AA amyloidosis in psoriatic arthritis. Ir J Med Sci. 2006;175:81–2. 12. Klünemann H, Schneider J, Linke RP, Stey C, Schröder S. Fatal generalized AA amyloidosis in mutilating psoriatic arthropathy. Pathologe. 1994;15:366–71 (German). 13. Ben Taarit C, Ajlani H, Ben Moussa F, Ben Abdallah T, Ben Maïz H, Khedher A. Renal involvement in ankylosing spondylitis: concerning 210 cases. Rev Med Interne. 2005;26:966–9 [French]. 14. Singh G, Kumari N, Aggarwal A. Prevalence of subclinical amyloidosis in ankylosing spondylitis. J Rheumatol. 2007;34:371–3. 15. Immonen K, Finne P, Hakala M, Kautiainen H, Pettersson T, Grönhagen-Riska C. No improvement in survival of patients with amyloidosis associated with inflammatory rheumatic diseases – data from the Finnish national registry for kidney diseases. J Rheumatol. 2008;35:1334–8. 16. Fernández-Nebro A, Olivé A, Castro MC, Varela AH, Riera E, Irigoyen MV, et al. Long-term TNF-alpha blockade in patients with amyloid A amyloidosis complicating rheumatic diseases. Am J Med. 2010;123:454–61. 17. Senel S, Kisacik B, Ugan Y, Kasifoglu T, Tunc E, Cobankara V. The efficacy and safety of etanercept in patients with rheumatoid arthritis and spondyloarthropathy on hemodialysis. Clin Rheumatol. 2011;30:1369–72. 18. Fiehn C, Andrassy K. Case number 29: Hitting three with one strike: Rapid improvement of psoriatic arthritis, psoriatic erythroderma, and secondary renal amyloidosis by treatment with infliximab (Remicade). Ann Rheum Dis. 2004;63:232. 19. Kobak S, Oksel F, Kabasakal Y, Doganavsargil E. Ankylosing spondylitis-related secondary amyloidosis responded well to etanercept: a report of three patients. Clin Rheumatol. 2007;26:2191–4. 20. Mpofu S, Teh LS, Smith PJ, Moots RJ, Hawkins PN. Cytostatic therapy for AA amyloidosis complicating psoriatic spondyloarthropathy. Rheumatology (Oxford). 2003;42:362–6. 21. Lehtinen K. Mortality and causes of death in 398 patients admitted to hospital with ankylosing spondylitis. Ann Rheum Dis. 1993;52:174–6.
www.elsevier.es/medicinaclinica
Original article
Amyloidosis complicating spondyloarthropathies: Study of 15 cases夽 Samantha Rodríguez-Muguruza a,∗ , Melania Martínez-Morillo a , Susana Holgado a , Xavier Saenz-Sarda b , Lourdes Mateo a , Xavier Tena a , Alejandro Olivé a a b
Servicio de Reumatología, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain Servicio de Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Badalona, Barcelona, Spain
a r t i c l e
i n f o
Article history: Received 8 April 2014 Accepted 19 June 2014 Available online 16 March 2016 Keywords: Secondary amyloidosis Spondyloarthropathy Renal failure
a b s t r a c t Background and objective: Secondary amyloidosis (AA) is a rare complication of rheumatic diseases. Objective: The aim of this study was to determine the frequency of symptomatic amyloidosis AA in patients with spondyloarthropathy. Patients and method: Retrospective study (1984–2013). We reviewed the medical records of patients with spondyloarthropathy who had a histological diagnosis of amyloidosis AA (15 patients). Results: We identified 1.125 patients with spondyloarthropathies. Fifteen (1.3%) patients with amyloidosis AA were recruited. It was suspected in 14 patients (93.3%) because of nephrotic syndrome in most of them: 14 were symptomatic (93.3%): 5 (33.3%) ankylosing spondylitis (AS), 5 (33.3%) spondylitis associated with inflammatory bowel diseases (IBD), 4 (26.7%) psoriatic arthritis, and one (6.7%) reactive arthritis. The mean disease duration was 23.9 years. Mortality after one and 5 years of follow-up was 30 and 50% respectively. Conclusions: The frequency of clinical amyloidosis AA in our patients was 1.3%. There was a marked male predominance, with AS or IBD. Clinical amyloidosis was diagnosed at a relatively late stage in spondyloarthropathy. ˜ S.L.U. All rights reserved. © 2014 Elsevier Espana,
Amiloidosis secundaria a espondiloartritis: estudio de 15 casos r e s u m e n Palabras clave: Amiloidosis secundaria Espondiloartritis Insuficiencia renal
Fundamento y objetivo: La amiloidosis secundaria (AA) es una complicación de enfermedades inflamatorias crónicas tales como las enfermedades reumáticas. El objetivo de este estudio fue evaluar la prevalencia de amiloidosis AA en una serie retrospectiva de pacientes con espondiloartritis. Pacientes y método: Estudio retrospectivo entre 1984-2013. Se revisaron las historias clínicas de los pacientes con diagnóstico de espondiloartritis y amiloidosis AA. Resultados: Se identificaron 1.125 pacientes con espondiloartritis. Quince (1,3%) presentaban amiloidosis AA: 14 (93,3%) fueron sintomáticos, en la mayoría de ellos se presentó como síndrome nefrótico. Cinco (33,3%) estaban diagnosticados de espondilitis anquilosante (EA), 5 (33,3%) de espondiloartritis asociada a enfermedad inflamatoria intestinal (EII), 4 (26,7%) de artritis psoriásica y uno (6,7%) de artritis reactiva. La media de edad de evolución desde el diagnóstico de espondiloartritis hasta el diagnóstico de amiloidosis ˜ ˜ y a los 5 anos ˜ fue del 30 y 50%, respectivamente. AA fue de 23,9 anos. La mortalidad al ano Conclusiones: En este estudio retrospectivo de pacientes con espondiloartritis, la prevalencia de amiloidosis AA sintomática fue del 1,24%. La mayoría fueron varones con una EA o espondiloartritis asociada a EII de larga evolución. El motivo más frecuente de sospecha del desarrollo de amiloidosis AA fue el síndrome nefrótico. ˜ S.L.U. Todos los derechos reservados. © 2014 Elsevier Espana,
夽 Please cite this article as: Rodríguez-Muguruza S, Martínez-Morillo M, Holgado S, Saenz-Sarda X, Mateo L, Tena X, et al. Amiloidosis secundaria a espondiloartritis: estudio de 15 casos. Med Clin (Barc). 2015;145:327–331. ∗ Corresponding author. E-mail address: [email protected] (S. Rodríguez-Muguruza). ˜ S.L.U. All rights reserved. 2387-0206/© 2014 Elsevier Espana,
328
S. Rodríguez-Muguruza et al. / Med Clin (Barc). 2015;145(8):327–331
Introduction Amyloidosis is a disease characterized by the extracellular deposition of a set of fibrillar proteins that have a common characteristic: they adopt a ß pleated sheet structure. There are 2 types, primary amyloidosis, mainly consisting of fragments of light immunoglobulin chains, and secondary amyloidosis (AA), consisting of protein A fibrils.1 AA amyloidosis is a complication of chronic inflammatory diseases whose diagnosis can be performed in the subclinical phase (incidentally as pathological finding), or the symptomatic phase, in which its manifestations vary according to the affected organ. An estimated 13% of patients with rheumatoid arthritis develop this complication throughout its progression, symptomatically,2 and up to 29% subclinically.3 Spondyloarthritis prevalence is lower and therefore not so well described; it is estimated that ankylosing spondylitis (AS) represents 1.1% in its symptomatic form4 and 7%5 in its asymptomatic manifestation. In the absence of comparative studies on the incidence of AA amyloidosis in different spondyloarthritis, and since a diagnostic coding system has only been available for 29 years, it was proposed to describe the clinical and laboratory characteristics, as well as the treatment received in a series of 15 patients with spondyloarthritis and AA amyloidosis diagnosed at a university reference site.
Patients and method Databases of the Rheumatology (CIPPER) and Pathology Departments of the Germans Trias i Pujol University Hospital, with a reference population of 850,000 inhabitants, were retrospectively reviewed (1984–2013). During this period, 1125 patients with spondyloarthritis were identified, all of them diagnosed according to current criteria. Patients treated in district hospitals within our area of reference with Rheumatology departments were not included in the study population. The diagnosis of AA amyloidosis was made by visualizing amyloid deposits under polarized light, characterized by its apple green with Congo red staining; likewise, immunochemistry was performed to confirm the subtype. Both, paper and electronic medical records of all patients were reviewed retrospectively. The following variables were collected: epidemiological data, clinical manifestations, treatment received, laboratory tests such as complete blood count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) (by nephelometry) and creatinine, area of diagnostic biopsy, treatment and progression. Patients with other entities that may be associated with AA amyloidosis, such as chronic infections or malignancies, at the time of diagnosis and during the course, were excluded.
Between 1985 and 1989, 3 patients were diagnosed with AA amyloidosis, 8 between 1990 and 1999, 3 between 2000 and 2010, and 1 patient in 2010. The average age at diagnosis for spondyloarthritis was 35.13 years (range 22–59), and 57.7 years (range 33–76) for AA amyloidosis. The average age of disease progression until the diagnosis of amyloidosis was 23.9 years (range 4–49). Ten patients (66.7%) had axial involvement, and 12 (80%), peripheral. Of the 12 patients who had genetic testing available, 6 (50%) were positive to B27 histocompatibility antigen (HLA-B27). The signs that made suspect the presence of AA amyloidosis in the 14 symptomatic patients (93.3%) were: nephrotic syndrome in 4 (28.6%), acute renal failure in 3 (21.4%), non-nephrotic range proteinuria in 3 (21.4%), chronic renal failure in 2 (14.3%), diarrhoea in one (7.1%) and haematuria in another (7.1%). In an asymptomatic patient the diagnosis was made incidentally while analysing the gallbladder after a cholecystectomy by gallstones; this patient had symptoms 1.5 years after the incidental diagnosis. The location of the AA amyloidosis’ diagnostic biopsy was: 6 in the rectal mucosa (40%), 4 in subcutaneous fat (26.7%), 3 renal (20%), 1 in the bladder (6.7%) and 1 in the gallbladder (6.7%). Three subcutaneous fat biopsies showed a false negative result. The diagnosis was confirmed by renal (2 patients) and rectal (1 patient) biopsy. The mean values of ESR and CRP before diagnosis of amyloidosis during the first hour were 65.4 mm and 25.22 mm mg/l, respectively. Serum creatinine values ranged between 0.8 and 3.2 mg/dl at the time of AA amyloidosis diagnosis and the last determination had variations between 1 and 4 mg/dl, regardless of dialysis status. Ten patients (66.7%) received chlorambucil and/or colchicine as a treatment for AA amyloidosis, with poor subsequent progression. Nine died, 2 from chronic renal failure and 7 from multiple organ failure secondary to sepsis. Five patients (33.3%) were treated with anti-tumour necrosis factor (TNF) ␣; infliximab was used in all. AA amyloidosis was the indication in 4 cases. Despite treatment with anti-TNF-␣, 2 patients required haemodialysis, both elderly at the time of AA amyloidosis diagnosis. The rest (60%) had an improvement in the figures of proteinuria and creatinine with respect to the time of diagnosis. One patient (20%) died of multiple organ failure secondary to pulmonary sepsis. During progression, 6 patients (40%) had end-stage renal failure requiring haemodialysis. Ten patients (66.7%) died: 2 due to causes secondary to renal failure and 8 due to multiple organ failure secondary to sepsis. Mortality was 30 and 50% at one and five years, respectively, for AA amyloidosis diagnosis.
Discussion Results During this period, 1125 patients with spondyloarthritis were visited at the Rheumatology Department, as follows: psoriatic arthritis 509 (45%), AS 263 (23%), spondyloarthritis associated with inflammatory bowel disease (IBD) 128 (11.3%), undifferentiated spondyloarthritis 190 (16.8%) and reactive arthritis 35 (3%). Of these, 41% were female and 59% male. Fifteen patients (1.3%) developed AA amyloidosis: 11 males (73.3%) and 4 women (26.7%). The type of Spondyloarthritis manifested was: 5 AS (33.3%), 5 spondyloarthritis associated with IBD (33.3%), 4 psoriatic arthritis (26.7%) and reactive arthritis (6.7%). The clinical and laboratory characteristics of the patients are summarized in Tables 1 and 2.
AA amyloidosis is a rare entity in spondyloarthritis. Its low incidence explains the limited number of patients obtained in a single hospital over a period of 29 years. A 1.1% incidence of symptomatic AA amyloidosis has been reported in AS patients,3 which correlates with the findings in this series (1.9%). Gratacos et al. describe that the subclinical form is present in 7% of patients.5,6 In this series, these data is not available, since clinical practice does not include biopsies of abdominal fat in asymptomatic patients. None of our cases of AA amyloidosis associated with AS was diagnosed incidentally. In 1998 Kagan et al. reported 39 cases of symptomatic AA amyloidosis in patients with psoriasis, 85% of them with associated arthropathy.5 Its actual incidence is not well documented, only a
Table 1 Clinical and analytical characteristics of 15 patients with spondyloarthropathy and secondary amyloidosis. 22/M
40/M
29/F
59/F
25/M
38/M
28/M
30M
Diagnosis
Psoriatic arthritis
Axial involvement Peripheral involvement HLA-B27 Anti-TNF treatment/indication Disease duration (years) Amyloid diagnosis age (years) ESR at diagnosis (mm) CRP at diagnosis (mg/dl) Biopsy location
Yes Polyarticular Positive Infliximab/arthritis 49 71 70 87 Gallbladder
Psoriatic arthritis No Oligoarticular NA No 28 68 27 3.8 Bladder
Psoriatic arthritis No Polyarticular Positive Infliximab/AA 4 33 125 80 Kidney
Ankylosing spondylitis Yes No NA No 37 62 NA NA Rectum
Ankylosing spondylitis Yes Polyarticular Positive No 6 44 NA NA Rectum
Ankylosing spondylitis Yes Polyarticular Positive Infliximab/AA 36 64 50 17.5 Rectum
Ankylosing spondylitis Yes Polyarticular Negative No 39 69 80 3.8 Rectum
Biopsy indication
Cholecystectomy
Haematuria Yes Yes/sepsis 1.2 1.9
Chronic renal failure No No 2.2 1.8
Proteinuria
Yes Yes/sepsis 1 5
Acute renal failure No Yes/sepsis 3 3.3
Diarrhoea
Dialysis Death/motive Creatinine at diagnosis Last creatinine
Nephrotic syndrome No No 1.1 1
Psoriatic arthritis No Yes Negative No 20 56 23 1.68 Subcutaneous fat Nephrotic syndrome No No 0.9 1
Yes Yes/sepsis NA 1.8
No Yes/CRF NA 3
AS onset age (years)/sex
24/M
40/M
40/F
30/M
44/M
41/M
37/F
Diagnosis
Ankylosing spondylitis Yes Polyarticular Positive No 21 45 50 6 Subcutaneous fat Acute renal failure No Yes/CRF 2.5 4
Spondyloarthropathy associated with IBD Yes No Negative Infliximab/AA 24 67 69 10.6 Kidney
Spondyloarthropathy associated with IBD Yes Polyarticular Negative No 20 60 82 14 Rectum
Spondyloarthropathy associated with IBD No Polyarticular Negative No 10 40 93 3.4 Rectum
Spondyloarthropathy associated with IBD Yes Polyarticular Positive Infliximab/AA 17 61 20 40 Kidney
Spondyloarthropathy associated with IBD Yes No Negative No 35 76 96 34.9 Subcutaneous fat
Acute renal failure
Nephrotic syndrome
Chronic renal failure
Nephrotic syndrome
Proteinuria
Reactive arthritis No Polyarticular NA No 13 50 NA NA Subcutaneous fat Proteinuria
Yes No 3.2 6
No Yes/sepsis 1.8 2.1
Yes Yes/sepsis 2.3 NA
No No 1.7 1.2
No Yes/sepsis 1.8 4.6
Yes Yes/sepsis NA NA
Axial involvement Peripheral involvement HLA-B27 Anti-TNF treatment/indication Disease duration (years) Amyloid diagnosis age (years) ESR at diagnosis (mm) CRP at diagnosis (mg/dl) Biopsy location Biopsy indication Dialysis Death/motive Creatinine at diagnosis Last creatinine
S. Rodríguez-Muguruza et al. / Med Clin (Barc). 2015;145(8):327–331
AS onset age (years)/sex
AS: spondyloarthropathy; F: female; HLA-B27: positive B27 histocompatibility antigen; ARF: acute renal failure; CRF: chronic renal failure; M: male; NA: not available; CRP: C-reactive protein; TNF: tumour necrosis factor; ESR: erythrocyte sedimentation rate.
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Table 2 Case selection algorithm. 1125 patients with spondyloarthritis
509 psoriatic arthritis (45%)
263 EA (23%)
128 spondylitis associated with IBD (11,5%)
3 AA amyloidosis symptomatic (0,6%)
5 AA amyloidosis symptomatic (1,9%)
5 AA amyloidosis symptomatic (3,9%)
190 spondyloarthritis 35 reactive arthritis undifferentiated (3%) (16,8%)
1 AA amyloidosis subclinical (2,8%)
+ 1 AA amyloidosis subclinical (0,2%)
AA: secondary; AS: ankylosing spondylitis; IBD: inflammatory bowel disease.
few isolated cases are available.6–12 There are no previous reports of subclinical AA amyloidosis in patients with psoriatic arthritis; in the present study, a patient is in this phase of the disease, with symptoms after 1.5 years of follow up. There are no previous communications in medical literature about reactive arthritis and AA amyloidosis. Table 3 describes the most relevant cases reported in the literature.4,13–16 In this case series, a marked predominance of males (73.3%) was evident, which is attributed to the increased frequency of spondyloarthritis and its greater aggressiveness in this sex. Symptomatic AA amyloidosis in AS usually occurs in patients with long-term disease, with significant axial and peripheral involvement as well as ESR and Bath Ankylosing Spondylitis Disease Activity Index greater at the beginning of the disease, and lower haemoglobin levels.6,17 Overall, the time of disease progression in our patients was over 10 years, similar to that found in previous series.4,6,7 However, one of our patients with psoriatic arthritis presented a symptomatic AA amyloidosis at 4 years of progression, possibly due to the aggressiveness of the disease, its mutilating character and a lack of appropriate therapeutic monitoring in the context of concomitant sociopathy. There is a clear association between HLA-B27 and spondyloarthritis. However, its frequency is different in each of them; in our cases, only 50% were positive. As numerous studies show, symptomatic AA amyloidosis occurs in a greater proportion of patients with peripheral joint involvement;5,6,17 in our case series,
80% had such involvement. As it is well known, forms of spondyloarthritis with peripheral involvement have less association with HLA-B27, which could explain the lower incidence of this genetic marker in our patients. The diagnosis of AA amyloidosis can be obtained by performing a biopsy of any organ; usually, with a preference for those in which there is suspicion of amyloid infiltration. In our case series, 40% of patients were diagnosed by performing rectal biopsy. Although a biopsy of subcutaneous fat is more accessible and less aggressive, in the past and according to protocol, our hospital used a rectal biopsy whenever there was suspicion of amyloidosis. A false negative was the result in 3 cases of abdominal fat biopsy. Although most clinical practice guidelines recommended an abdominal fat biopsy as first diagnostic test to screen for amyloidosis, its sensitivity varies greatly depending on the fat extraction technique and the sample processing. In this study, 2 of the 3 false positives were due to the sample being insufficient. Significantly, in this series, the mean age at diagnosis of AA amyloidosis was 57.7 years, higher than that found in previous series.4,13–16 A downward trend in the incidence of symptomatic AA amyloidosis over the years is observed in this study, possibly due to better control of the underlying disease with the use of anti-TNF-␣ treatment. The approach of AA amyloidosis in inflammatory arthropathy is based on treating the underlying disease. As regards spondyloarthritis, there are cases and small series showing that TNF-␣ antagonists improve clinical signs and symptoms and prevent renal function deterioration.4,6–13,16,18,19 In the present series, 5 patients required the use of anti-TNF-␣ and amyloidosis was the indication in 4 of them. The outcome was favourable in 60% of them, or similar decline in creatinine levels at diagnosis. The other 2 patients required haemodialysis possibly due to the long progression of the disease and advanced age at diagnosis. In the other patient, the lack of improvement despite treatment with anti-TNF-␣ could be due to the fact that AA amyloidosis onset was in the context of acute renal failure. The use of biological drugs could not be considered in the other 10 patients, as they were the oldest cases, prior to the availability of those drugs. Notably, there have been reports of improvement with colchicine and chlorambucil.6,19 AA amyloidosis has a high mortality due to end-stage renal disease, infectious processes and intestinal perforation or bleeding. Studies conducted prior to the availability of biologic drugs show that AA amyloidosis was the direct cause of death in 13% of patients with AS, and that it reduced the average life 2.37 years, with a 30% survival rate at 5 years.20,21
Table 3 Relevant cases of spondyloarthritis and secondary amyloidosis described in literature. Spondyloarthritis, n
AA amyloidosis, n
Age at diagnosis of AA amyloidosis, average in years
Progression time in years
Biopsy site
Symptoms
Treatment
Nephrotic syndrome and non-nephrotic proteinuria Subclinical Nephrotic and non-nephrotic proteinuria, ARF Subclinical
ND
Ben Taarit et al.13
AS/210
6
36.8
ND
Renal (5), labial (1)
Singh et al.14 Dönmez et al.4
AS/72 AS/730
5 8
39.2 48
15.2 18.6
Subcutaneous fat Rectal (3), renal (1)
Immonen et al.15
Psoriatic Arthritis/70
3
36
41.857
Fernandez-Nebro et al.16 Gratacos et al.6
Psoriatic arthritis/ND
4
52
16
Colon (1), intestine (1), ND (10) Renal
10
57
24.1
Subcutaneous fat
AS/137
AA: secondary; AS: ankylosing spondylitis; ARF: acute renal failure; ND: not determined.
ARF, proteinuria Subclinical
ND Infliximab, etanercept, adalimumab Tocilizumab Infliximab, etanercept ND
S. Rodríguez-Muguruza et al. / Med Clin (Barc). 2015;145(8):327–331
In the present series, AA amyloidosis was the direct cause of death in only 2 patients; the majority (8 cases) died from secondary infections. Although it is a study which includes a substantial number of patients with ankylosing spondyloarthritis and for a long period of time, this is limited by its retrospective nature and the relative small number of patients due to of the low incidence of this disease. In conclusion, AA amyloidosis should be suspected in patients with longstanding spondyloarthritis with persistently elevated acute phase reactants, proteinuria or renal failure. The treatment is controversial and is based on case reports and clinical experience; however, the role of anti-TNF-␣ is promising. Conflicts of interest The authors declare that they have no conflicts of interest. References 1. Maduell F, Calco C, Hernández-Jara J, García Pérez H, Torregosa E, Rius A. Secondary amyloidosis (AA) and renal disease. Nefrologia. 2003;23:321–6. 2. Mueller OS. Amyloidosis. Current rheumatology, diagnosis & treatment. 2nd ed. USA: McGraw Hill; 2007. 3. Wiland P, Wojtala R, Gooacre J, Szechinski J. The prevalence of subclinical amyloidosis in Polish patients with rheumatoid arthritis. Clin Rheumatol. 2004;23:193–8. 4. Dönmez S, Pamuk ÖN, Pamuk GE, Aydo˘gdu E, Inman R. Secondary amyloidosis in ankylosing spondylitis. Rheumatol Int. 2013;33:1725–9. 5. Kagan A, Husza’r M, Frumkin A, Rapoport J. Reversal of nephrotic syndrome due to AA amyloidosis in psoriatic patients on long-term colchicine treatment. Case report and review of the literature. Nephron. 1999;82:348–53. 6. Gratacos J, Orellana C, Sanmarti R, Sole M, Collado A, Gomez-Casanovas E, et al. Secondary amyloidosis in ankylosing spondylitis. A systematic survey of 137 patients using abdominal fat aspiration. J Rheumatol. 1997;24: 912–5.
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7. Bergis M, Dega H, Planquois V, Benichou O, Dubertret L. Amyloidosis complicating psoriatic arthritis. Ann Dermatol Venereol. 2003;130:1039–42 (French). 8. Qureshi MS, Sandle GI, Kelly JK, Fox H. Amyloidosis complicating psoriatic arthritis. Br Med J. 1977;2:302. 9. Lambert JR, Wright V. Eye inflammation in psoriatic arthritis. Ann Rheum Dis. 1976;35:354–6. 10. Pérez Silvestre J, Campos Fernández C, Baixauli Rubio A, Calvo Catalá J, GonzálezCruz MI, Herrera Ballester A. Psoriatic arthritis complicated with secondary amyloidosis. An Med Interna. 2008;25:247–9 [Spanish]. 11. Ryan JG, Dorman AM, O’Connell PG. AA amyloidosis in psoriatic arthritis. Ir J Med Sci. 2006;175:81–2. 12. Klünemann H, Schneider J, Linke RP, Stey C, Schröder S. Fatal generalized AA amyloidosis in mutilating psoriatic arthropathy. Pathologe. 1994;15:366–71 (German). 13. Ben Taarit C, Ajlani H, Ben Moussa F, Ben Abdallah T, Ben Maïz H, Khedher A. Renal involvement in ankylosing spondylitis: concerning 210 cases. Rev Med Interne. 2005;26:966–9 [French]. 14. Singh G, Kumari N, Aggarwal A. Prevalence of subclinical amyloidosis in ankylosing spondylitis. J Rheumatol. 2007;34:371–3. 15. Immonen K, Finne P, Hakala M, Kautiainen H, Pettersson T, Grönhagen-Riska C. No improvement in survival of patients with amyloidosis associated with inflammatory rheumatic diseases – data from the Finnish national registry for kidney diseases. J Rheumatol. 2008;35:1334–8. 16. Fernández-Nebro A, Olivé A, Castro MC, Varela AH, Riera E, Irigoyen MV, et al. Long-term TNF-alpha blockade in patients with amyloid A amyloidosis complicating rheumatic diseases. Am J Med. 2010;123:454–61. 17. Senel S, Kisacik B, Ugan Y, Kasifoglu T, Tunc E, Cobankara V. The efficacy and safety of etanercept in patients with rheumatoid arthritis and spondyloarthropathy on hemodialysis. Clin Rheumatol. 2011;30:1369–72. 18. Fiehn C, Andrassy K. Case number 29: Hitting three with one strike: Rapid improvement of psoriatic arthritis, psoriatic erythroderma, and secondary renal amyloidosis by treatment with infliximab (Remicade). Ann Rheum Dis. 2004;63:232. 19. Kobak S, Oksel F, Kabasakal Y, Doganavsargil E. Ankylosing spondylitis-related secondary amyloidosis responded well to etanercept: a report of three patients. Clin Rheumatol. 2007;26:2191–4. 20. Mpofu S, Teh LS, Smith PJ, Moots RJ, Hawkins PN. Cytostatic therapy for AA amyloidosis complicating psoriatic spondyloarthropathy. Rheumatology (Oxford). 2003;42:362–6. 21. Lehtinen K. Mortality and causes of death in 398 patients admitted to hospital with ankylosing spondylitis. Ann Rheum Dis. 1993;52:174–6.