Lupus (2002) 11, 379± 383 www.lupus-journal.com

PAPER

Antiribosomal P protein antibodies in Chilean SLE patients: no association with renal disease L Massardo1*, P Burgos2, ME Martõ´nez1, R Pe´rez1, M Calvo3, J Barros4, A Gonza´lez2 and S Jacobelli1

Departamento de Inmunologia Clõ´nica y Reumatologõ´a, Facultad de Medicina, PontiŽ cia Universidad Cato´lica de Chile, Santiago, Chile; 2Centro de Regulacio´n Celular y Patologõ´a, Facultad de Ciencias Biolo´gicas, PontiŽ cia Universidad Cato´lica de Chile, Santiago, Chile; 3 Departamento de Medicina Interna, Facultad de Medicina, PontiŽ cia Universidad Cato´lica de Chile, Santiago, Chile; 4 Departamento de Psiquiatrõ´a, Facultad de Medicina, PontiŽ cia Universidad Cato´lica de Chile, Santiago, Chile

1

The objective of this work was to determine the frequency and clinical associations of antiribosomal P protein antibodies (Anti-P) in a cohort of Chilean patients with systemic lupus erythematosus (SLE). Between 1996 and 1998, 141 consecutive patients with SLE were examined prospectively according with a standard protocol. Disease activity was measured by MEX-SLEDAI in 138 patients. Anti-P positivity was determined by double immune diffusion or Western blot and ELISA. Anti-P was found in 21 (15%) patients. In the Anti-P positive patients recent onset SLE (disease duration of 1 year or less) was more frequent (P ˆ 0.018). Anti-P was found in 23% of 83 patients with active SLE vs 4% of the 55 patients with inactive SLE (Yates corrected P ˆ 0.00479). An association with anti-dsDNA antibodies by Farr assay was observed. Anti-P positive patients had a median Farr of 65 IU=ml (1.4 – 1240) and Anti-P negative of 12 IU=ml (1.4 – 992; Pvalue ˆ 0.0084). During the study only two patients had lupus psychosis and they were Anti-P positive. No association was found with liver disease (six patients, two with Anti-P antibodies) or active glomerulonephritis(22 patients, four with Anti-P). Our data shows that the presence of AntiP antibodies supports the clinical diagnosis of lupus psychosis. Lupus (2002) 11, 379–383. Key words: antiribosomal P antibodies; lupus; clinical associations

Introduction Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of a number of circulating autoantibodies. It has been known for a long time that patients with SLE make antibodies that bind to three ribosomal phosphoproteins, P0, P1 and P2, with molecular weights of 35, 19 and 17 kDa.1 These autoantibodies seem to be speciŽ c for SLE.2–7 The frequency of antiribosomal P protein antibodies (Anti-P) in patients with SLE from the USA and Europe has been reported to be 10 – 20%,3,4,8–10 whereas reports on Asian populations describe variations from 38 to 50%.6,11,12 Even higher prevalences of these antibodies have been described in children with SLE.13 Several studies have shown that anti-P antibodies are associated with clinical disease activity 6,10,13–15

and also with particular clinical manifestations, more clearly with neuropsychiatric (NP) disease,3–5,10,11,16– 18 although there are reports where such associations have not been found.6,9,19,20 An association with liver or kidney disease has also been described by one group of investigators,13–15,21–23 but not by others.4,9,10 Most of the clinical associations have been found in retrospective studies. Here we present a prospective study on a cohort of 141 SLE patients, in which we have looked for Anti-P antibodies using Ouchterlony immune diffusion, Western blot and ELISA tests. We found that these autoantibodies are associated with active disease, lupus psychosis, and anti-dsDNA levels, but not with renal or liver disease.

Patients and methods Patient selection and chart review

*Correspondence: L Massardo, Departamento de Inmunologõ´a Clõ´nica y Reumatologõ´a, Escuela de Medicina, PontiŽ cia Universidad Cato´lica de Chile, Marcoleta 367, Casilla 114-D, Santiago, Chile. E-mail: [email protected] Received 1 November 2001; accepted 8 April 2002 # Arnold 2002

In this prospective cross-sectional study 141 consecutive unselected patients with SLE were examined between April 1996 and September 1998; 14 were men and 127 were women, with median disease 10.1191=0961203302lu209oa

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duration from the Ž rst symptoms of SLE of 5 years (0.1 – 31). The median age was 33 years (6 – 77). All patients fulŽ lled the ACR criteria for the diagnosis of SLE.24 Disease activity of SLE at the time of the blood sample tested for Anti-P antibody was evaluated in 138 patients according to the Mexican SLE Disease Activity Index (MEX-SLEDAI).25 Eightythree patients had active disease (MEX-SLEDAI score > 0). Medical records were reviewed in detail regarding various disease manifestations of SLE, such as NP manifestations and liver and kidney disease. During the study, NP manifestations according to the MEXSLEDAI deŽ nition were found in nine patients: two patients with psychosis (severe behavioural disturbance requiring hospitalization or the use of psychotropic drugs or both), two with cerebrovascular accident (CVA), one with organic brain syndrome (OBS), one with transverse myelitis, two with cranial nerve disorder and one with mononeuritis multiplex and headache. Three patients had major depression (a severe depressed mood change or lost of interest in nearly all activities who required hospitalization or the use of antidepressive drugs) attributed to active SLE. Depression is not a component of the MEX-SLEDAI activity index, however. In all, the incidence of NP manifestations was 8.5% (12 patients). Lupus hepatitis was deŽ ned as any persistent elevation of the liver enzymes not explained by the use of drugs or hepatitis B or C virus. During the study the frequency of hepatitis was 4% (six patients). Active renal disease according with the MEXSLEDAI deŽ nition (casts: heme granule or erythrocyte, hematuria, new onset proteinuria > 500 mg=24 h or a creatinine increase > 0.5 mg=dl) was found in 22 (16%) patients. Renal biopsy was performed in 17 patients and classiŽ ed in: WHO Class III, four patients; WHO Class IV, 12 patients; and WHO Class V, one patient. In 126 patients we categorized the renal functional stage in four strata as previously described.26 There were 90 (71%) patients with stage 1 — serum creatinine level < 1.3 mg=dl and proteinuria < 1 g=l; 10 (8%) patients with stage 2 — serum creatinine < 1.3 mg=dl and proteinuria ¶ 1 g=l; nine (7%) patients with stage 3 — serum creatinine between 1.3 and 3 mg=dl; and six (5%) patients with stage 4 — serum creatinine level > 3 mg=dl. The anti-double-stranded DNA antibody levels were measured by Farr assay using 125I (Diagnostics Products Corporation, Los Angeles, CA, USA) in the sera of 131 patients; normal value is lower than 10.4 IU=ml.27 Immunosuppressive treatment was assessed in 84 active SLE and in 55 inactive patients. We registered

the dose of prednisone equivalent in mg=day, and the use of cytotoxic drugs and antimalarials. Measurement of Anti-P All sera were studied for Anti-P antibodies by Ouchterlony double diffusion against ribosomal rat liver. Western blot assays were done using rat ribosome extract as substrate, overlaid with patient serum followed by protein A-alkaline phosphatase conjugate.28 Anti-P enzyme-linked immunosorbent assay was measured with a commercial kit (ImmuLisa Anti-ribosomal P Antibody ELISA IMMCO Diagnostics, Buffalo, USA) with a negative or intermediate values between 0 and 25 enzyme units=ml (EU=ml). A positive Anti-P ribosomal serum (kindly donated by Dr Morris Reichlin from the Oklahoma Medical Research Foundation) was used as a control. Sera from 68 healthy individuals were used as controls. From the 141 SLE patients tested, the Ouchterlony double diffusion was positive in four, with a precipitation band with identity in front of the positive P ribosomal control. Western immunoblotting was positive in 21 patients, with the three bands of 38, 19 and 17 kDa. As deŽ ned by Arnett and Reichlin, we considered Anti-P positive only where the sera were positive by Ouchterlony double diffusion or by Western blot and ELISA.23 Statistical analyses Data are presented with median and range in parentheses. Fisher’s exact test, chi-square with Yate’s correction, ANOVA and Kruskal – Wallis tests were used where indicated to test statistical signiŽ cance in lupus patients using the EPI INFO 6.0 statistical software.

Results From a total of 141 consecutive patients with SLE, 21 (15%) patients were anti-ribosomal P protein antibodies-positive by Western blot and ELISA, four of them were also Ouchterlony positive. By ELISA the median (range) EU=ml values of 21 Anti-P-positive patients was 83 (45 – 573). For the 120 Anti-P negative patients it was 8 (0 – 48), and for the 68 controls it was 3.4 (0 – 24). The 21 patients with Anti-P( ‡ ) had a lower disease duration from the Ž rst symptoms of SLE, with a median of 1 year (0.1 – 17) compared with 5 years (0.1 – 31) in the 117 patients without these antibodies (ANOVA test P-value ˆ 0.024; Table 1). No association was observed with juvenile onset of SLE. Eight patients were younger than 18 years in the series and only one of them (13%) was Anti-P( ‡ ).

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Table 1 Clinical features of 138 consecutive patients with SLE at the time of anti-P determination Antiribosomal P antibodies

Women:men Age, years; median (range) Years after disease onset; median (range) MEX-SLEDAI score; median (range) Number with active SLE (%)a Neuropsychiatric involvement (including depression) Lupus psychosis Lupus hepatitis Renal disorder

Positive (n ˆ 21)

Negative (n ˆ 117)

17:4 28 (17 – 77) 1 (0.1 – 17)

107:10 34 (6 – 69) 5 (0.1 – 31)

7 (0 – 16)

2 (0 – 15)

P-value NS NS 0.024 0.000242

19 (90%) 4 (19%)

64 (46%) 8 (7%)

0.0044 NS

2 (10%) 2 (10%) 4 (19%)

0 (0%) 4 (3%) 18 (15%)

0.022 NS NS

a

Patients with active SLE had a MEX-SLEDAI score > 0.

Eighty-three of the 138 patients assessed by MEXSLEDAI had active SLE at the time of the blood test. In these patients the frequency of Anti-P( ‡ ) was 19 (23%), signiŽ cantly higher than two of 55 (4%) patients with inactive SLE (Yate’s corrected Pvalue ˆ 0.0044). Not a single component of the index could be identiŽ ed as more common. The MEX-SLEDAI score was median 8 (2 – 16) in the 19 Anti-P( ‡ ), and 6 (1 – 15) in the 62 Anti-P ( 7 ) (Kruskal – Wallis test P-value ˆ 0.08). Of the 21 patients with Anti-P( ‡ ), four (19%) had an NP disorder: two patients with psychosis, one with cranial nerve disorder, and one with major depression. Of the 120 Anti-P ( 7 ) patients eight (7%) had an NP disorder: two CVA, one cranial nerve disorder, one OBS, one transverse myelitis, and one mononeuritis multiplex and headache; there were also two patients with major depression. No statistical difference was found. However, a signiŽ cant difference appeared when only the presence of lupus psychosis was compared. Two patients with active lupus psychosis were found in the 21 Anti-P( ‡ ) group and none in the 117 Anti-P ( 7 ) group (Fisher exact test Pvalue ˆ 0.022; Table 1). Another Ž nding in this group with positive Anti-P antibodies was hepatitis in two patients, compared with four of the 117 without the Anti-P antibodies (Pvalue ˆ NS). The two Anti-P( ‡ ) patients with hepatitis had recent onset SLE, one with vasculitis and hematological manifestations and the other with lupus psychosis and fever. An active renal disorder was studied in 138 patients. It was found in four (19%) of the 21 AntiP ( ‡ ) SLE patients and in 18 (15%) of the 117 AntiP( 7 ) patients (P value ˆ NS). No differences were found in frequencies of past history of renal disease, World Health Organization lupus nephritis type biop-

sies or in the renal function strata at the time of Anti-P study. The six patients who were in strata 4 (serum creatinine level > 3 mg=dl) were Anti-P( 7 ). Anti-dsDNA antibodies assessed by the Farr assay were studied in 131 patients. The 19 patients with a positive Anti-P had a median Farr of 65 IU=ml (1.4 – 1240), compared with a median of 12 IU=ml (1.4 – 992) in the 112 Anti-P( 7 ) group. This difference was statistically signiŽ cant (Kruskal – Wallis test Pvalue ˆ 0.0084). The Farr assay was higher on 17 Anti-P( ‡ ) SLE active patients, compared with 62 Anti-P( 7 ) SLE active patients with a median of 95 (1.4 – 1240) IU=ml and 19 (1.4 – 730), respectively (Kruskal – Wallis test P-value ˆ 0.0362). Treatment was assessed in 83 active SLE. Eightythree percent received steroids. The median dose of prednisone equivalent was 15 (0 – 1250) mg=day, 26% were using cytotoxic drugs (17% with cyclophosphamide, 9% with metothrexate or azathioprine), and 57% used antimalarial drugs. Eighty percent of the 55 inactive SLE patients were on steroids with a median prednisone equivalent dose of 5 (0 – 30) mg=day, 9% were on cytotoxics (4% with cyclophosphamide), and 60% used antimalarials. Patients with active SLE received higher doses of prednisone and used more cytotoxics drugs than patients with inactive SLE (P-value ˆ 0.000135 and P-value ˆ 0.028, respectively).

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Discussion In this prospective study we found that the frequency of Anti-P ribosomal antibodies was 15% in 141 unselected consecutive adult Chilean patients with SLE, which is similar to what has been published for Caucasian populations.3,4,8–10 Anti-P antibodies were more frequent in the patients with active disease, 19 of 83 (23%), than in those with inactive SLE, two of 55 (4%), as has been reported.6,10 Even though Anti-P positivity was associated with active SLE, not a single component of the MEXSLEDAI was identiŽ ed as more frequent in Anti-P patients, including neurologic disorder or active renal disease. Cytotoxic treatment was more commonly used in active SLE so it is difŽ cult to attribute to treatment the low levels of Anti-P in inactive patients. Since the report of Bonfa et al,5 the association with lupus psychosis has been extensively studied. Some studies have supported those results,4,10,11,16–18 but others have not.9,19,20 There are numerous methods for determining antibodies to the ribosomal P proteins which differ in sensitivity and speciŽ city.29 It has been postulated that a larger purity of the ribosomal P peptide would explain the positive correLupus

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lation found with NP manifestations. 18 Besides the technical aspects that might account for the discrepancies, others have suggested that clinical deŽ nitions of lupus psychosis, incomplete registrations in retrospective studies, and ethnic compositions of studied populations, are probably responsible for the different conclusions.20 In our prospective study we used the criteria of Arnett and Reichlin for the deŽ nition of a positive result, conŽ rming a positive ELISA with immunoblot.23 Only two patients with SLE and psychosis attended our Rheumatology clinic in 2.5 years and were Anti-P( ‡ ) (two of 21 vs 0 of 117; Pvalue ˆ 0.022). Both patients had recent onset lupus and one of them also had lupus hepatitis. Besides these two patients, another patient positive for Anti-P antibodies had had lupus psychosis 11 months previously. Other NP manifestations were not associated with Anti-P. In three cases there was a major depression attributed to SLE activity and one was AntiP( ‡ ). We could not conŽ rm the association of Anti-P antibodies with hepatitis due to SLE.21–23 Lupusrelated hepatic disease must be distinguished from hepatitis caused by drugs, toxins, viral, and autoimmune illnesses. This is a difŽ cult clinical distinction, since lupus patients are prone to hepatitis from various different aetiologies. Of the six cases of hepatitis attributed to SLE only two were Anti-P positive and one of them also had psychosis. However, with only six cases of hepatitis in the series we cannot make a statement that liver disease is not associated with Anti-P antibodies. Antiribosomal P antibodies have also been associated with lupus nephritis.14,15,22 Studies that have speciŽ cally addressed this issue, however, have been few and involved a small number of patients with variable results. We did not Ž nd an association with active nephritis. At the time of the study, 22 patients had active renal disease and four had Anti-P antibodies (18%). In the 33 patients with a past history of renal disease, Anti-P was found in two patients (6%). Our data agrees with those of Schneebaum et al and Van Dam et al who did not describe a relationship between nephritis and Anti-P.4,9 An interesting Ž nding was the positive association between anti-dsDNA by Farr and Anti-P found in this series. Both antibodies commonly occur together10 and similarly vary with disease activity. 14,15,30 Our patients with active SLE and positive Anti-P had higher levels of anti-dsDNA compared with active patients with negative Anti-P antibodies (P-value < 0.03). Since patients had similar MEX-SLEDAI scores, the activity of the disease is probably not the only factor involved in this association. It might be

related to tissue damage rather than activity, as suggested by Takeda et al.31 Recently, it has been shown that a subset of anti-dsDNA antibodies recognized a glutamate receptor in the cellular membrane of neurons mediating apoptotic death.32 It seems unlikely that anti-dsDNA could recognize the P epitope, thus explaining the association between Anti-P and anti-dsDNA, because cross-reaction of antidsDNA with the P epitope is infrequent.33 At present there is no mechanistic hypothesis that could explain the clinical associations of Anti-P. Similarly to what has been described for antidsDNA, cross-reactivity with proteins at the cell surface might be a determinant that remains to be elucidated. We think that the clinical relevance of antiribosomal P antibodies is the addition of one piece of evidence to other available clinical information. There are many limitations to the antiribosomal antibody test. When negative, it has little value. When positive, however, this antibody supports a diagnosis of SLE and a positive result in the appropriate situation will deŽ nitely support a suspicion of lupusrelated psychosis.

Acknowledgements We acknowledge Santiago Rivero, MD for reviewing the manuscript, MSc, Ximena Soza for the Ouchterlony, MSc Franklin Juica for starting the ELISA. Also we thank Miguel Gutie´rrez MD, Francisco Gutie´rrez MD, Francisco Radriga´n MD and Alex Vargas MD for sharing the clinical data of their patients, and Luis Villarroel, MSc for the statistics. The authors would like to thank Dr Morris Reichlin from the Oklahoma Medical Research Foundation, USA, for the Anti-P positive sera, and Mrs Teresa Cole for her help in the correction of the manuscript. This work received Ž nancial support from the Fondo Nacional de Investigacio´n CientiŽ ca y Tecnolo´gica (FONDECYT), grant nos 1961068 and 2990025, Fondo Nacional=Areas prioritarias (FONDAP), Grant no. 13980001, and the Millenium Institute for Fundamental and Applied Biology, Ž nanced in part by the Ministerio de PlaniŽ cacio´n y Cooperacio´n de Chile.

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