120037721_IPH_26_00_R2_041504
1 2
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY Vol. 26, No. 0, pp. 1–6, 2004
3
5
Lupus Nephritis Improvement After Anti-tumour Necrosis Factor Alpha Monoclonal Antibody (Infliximab) Treatment for Crohn’s Disease: A Case Report
6 7
M. Principi,1 A. Di Leo,1 M. Ingrosso,1 A. Pisani,1 S. Marangi,1 A. Amoruso,1 C. Panella,2 A. Francavilla,1 and Enzo Ierardi, M.D.2,*
4
8 9 10 11 12
1
Gastroenterology Section, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy 2 Gastroenterology Section, Department of Medical and Occupational Sciences, University of Foggia, Foggia, Italy
13
ABSTRACT
14 15 16 17 18 19 20 21 22 23 24
Association between Crohn’s disease (CD) and lupus nephritis is very rare and, to the best of our knowledge, it has been described only once. We report here a clinical case of CD occurred in a young woman 8 years after a diagnosis of lupus nephritis according to clinical, laboratory and histological criteria. CD was unresponsive to steroids and immunosuppressants and, therefore, the patient was treated with antitumour necrosis factor alpha monoclonal antibody (Infliximab). This therapy led to the remission of both CD (50% of Crohn’s Disease Activity Index—CDAI—decrease) and lupus nephritis (disappearance of pyuria in absence of infection, significant increase of serum albumin and improvement of renal function tests). The immunological background of both diseases has to be taken into account to explain either the association of the two disorders or the therapeutic response. Moreover, this
*Correspondence: Enzo Ierardi, M.D., Cattedra di Gastroenterologia, Universita` di Foggia c/o Ospedali Riuniti, Viale L. Pinto, 71100 Foggia, Italy; Fax: +39-(0)-881-747884; E-mail: e.ierardi@ virgilio.it. 1 DOI: 10.1081/IPH-120037721 Copyright D 2004 by Marcel Dekker, Inc.
0892-3973 (Print); 1532-2513 (Online) www.dekker.com
120037721_IPH_26_00_R2_041504
2
Principi et al.
25 26
clinical case confirms and extends the concept that in patients with CD a more accurate detection of autoimmune associated disorders is required.
27
Key Words:
Lupus nephritis; Infliximab; Crohn’s disease; Steroids.
28
INTRODUCTION
29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56
The association between inflammatory bowel diseases (IBD) and autoimmune disorders is well known. In this regard, a recent study, performed in a population affected by IBD lasting for at least 10 years, pointed out that iritis/uveitis and erythema nodosum, are similarly present in Crohn’s disease (CD) and ulcerative colitis, whereas other manifestations, such as ankylosing spondylitis and pyoderma gangrenosum, are predominantly observed in CD.[1] Besides a series of diseases, which have conventionally stated as extraintestinal IBD associated disordes, there are uncommon associations such as that involving systemic lupus erythematosus (SLE) and CD which have been infrequently reported as isolated case reports.[2 – 5] In detail, the combination of CD and lupus nephritis has been described only once.[6] Often the treatment of IBD results in the improvement of an associated disorder, such as spondyloarthropathy and cutaneous manifestations.[7,8] Indeed, the recent statements about the key role of tumour necrosis factor alpha (TNFa) in the pathogenesis of CD,[9 – 11] as well as the use of anti-TNFa monoclonal antibody (Mo.Ab) (Infliximab) in the therapy of this disorder[12,13] has prompted investigations of the effects of this Mo.Ab on autoimmune IBD associated disorders. Convincing data on the treatment of ankylosing spondylitis with this drug have been reported by Braun et al. in a 12-week placebo-controlled multicentre study on 70 randomized patients.[14] Joint function and quality of life significantly improved with Infliximab when compared to placebo. In another study, Van den Bosch et al. reported that the number of swollen joints dropped after Infliximab treatment in patients with CD associated to spondyloarthropathies.[7] The prevalence of cutaneous manifestations in IBD is higher in CD than in UC and this aspect has been recently emphasized in a report by Tromm et al.[8] Even in this field, current literature has shown a beneficial effect of Infliximab on Gangrenosum Pyoderma.[13] On these bases we believe of relevance to describe the case of a patient affected by an association of CD and lupus nephritis, who experienced a beneficial effect of Infliximab on both disorders.
57
CASE REPORT
58
Patient’s Clinical History
59 60 61 62
The patient, a 24 year old woman, was affected by lupus nephritis (WHO class IV) diagnosed according to well stated clinical, laboratory and histological findings, which occurred in paediatric age (14 years) and. In detail, clinical features of nephrosic syndrome (blood pressure increase, oedema) were present, while laboratory data
120037721_IPH_26_00_R2_041504
Lupus Nephritis After Infliximab Treatment for Crohn’s Disease 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84
3
showed increase of blood urea nitrogen (BUN) and creatininaemia, urinary protein loss, reduction of complement factors, anti-nucleous and anti-DNA antibodies positivity. Finally renal histology showed diffuse glomerulonephritis with active necrotizing and sclerosing lesions. The patient was treated with Cyclophosphamide, withdrawn for adverse events, Methylprednisolone (100 mg/day) and Azatioprine (100 mg/day). During therapy, the renal disorder did not result in a continuous remission showing several clinical and laboratory relapses. After some years, at the age of 22, CD onset occurred in addition to lupus nephritis. Activity was severe (CDAI 380, normal value < 200) and clinically abdominal pain and hematochezia were present associated to oedema of lower limbs due to severe hypoalbuminemia (2.1 g/dl). The diagnosis of CD was performed according to endoscopy/histology and small bowel X-ray examination and the disease involved terminal ileum and transverse/descending colon. Simultaneously, the activity of renal disease was revealed by the presence of urinary casts, red and white blood cells in absence of infection. Conventional immunosuppressive therapy (steroid plus azatioprine firstly and cyclosporin successively) was uneffective. Tacrolimus was even administered, but unfortunately serum therapeutic levels were not reached probably for a change in drug kinetics due to hypoalbuminemia. Total parenteral nutrition and albumin infusion were necessary. Infliximab was then administrated at the dose of 5 mg/Kg/iv (weeks 0, 2, 6 and 14).
Figure 1. (a) BUN (enzymatic reaction/spectrophotometry; values expressed as mg/dl) pattern during Infliximab therapy. (b) creatininemia (colorimetric reaction after deproteinization; values expressed as mg/dl) pattern during Infliximab therapy. (c) urinary protein loss (colorimetric reaction, values expressed as g/24 hours) during Infliximab therapy.
120037721_IPH_26_00_R2_041504
4
Principi et al.
85
Results
86 87 88 89 90 91 92 93 94 95
Following therapeutic regimen with Infliximab, an impressive CD remission was achieved, as demonstrated by a significant decrease of CDAI until reaching a normal value (190). Simultaneously an improvement of nephritis was evident with disappearance of peripheral oedema and a decrease of blood pressure values (from 170/ 100 to 130/90 mmHg). Laboratory findings showed a marked reduction of BUN, creatininemia and urinary protein loss (Fig. 1a – c). A 25-fold reduction of white blood cells in urine was finally seen (data not shown). These benefits were maintained during a follow-up of 13 months. Actually the patient is assuming only mesalazine (2400 mg daily) and methylprednisolone (8 mg daily) because of a complete remission of both renal and intestinal disorders.
96
DISCUSSION
97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126
It is known that kidney is involved in the course of SLE. In 1980, Shearn et al. emphasized that disease may mimic an idiopathic glomrulonephritis in less than a quarter of patients.[15] In this case, the detection of specific laboratory markers, such as anti-nucleus and anti-DNA antibodies, as well as the reduction of circulating complement factors is essential for a correct diagnosis, which needs to be completed by the performance of a renal biopsy. In the case we described in this paper, renal failure was the only sign of lupus disorder and, moreover, CD occurred 8 years after nephritis onset. This association is very rare, since it has been described only once in a report from Sugimoto et al.[6] In this case, unlike ours, kidney disorder followed the diagnosis of CD. A further peculiarity of our case is that administration of Infliximab, because of the patient’s unresponsiveness to every therapeutic attempt, led to a concomitant remission of lupus nephritis. The remission was strongly suggested by clinical and laboratory findings even if not confirmed by histological examination. In this last respect, kidney biopsy was not performed since the major aim of Infliximab therapy was the cure of CD. Nevertheless, as an indirect index of the decrease of active renal inflammation, the disappearance of urinary casts and pyuria (in absence of infection), i.e., a 25-fold reduction of white blood cell count, was taken into account. According to very recent findings, SLE and CD differ at the cytokine level in terms of IL-2 and IL-10 production. In SLE IL-2 production is decreased,[16] while in CD IL-2 production is increased.[17] Instead, a putative low production of IL-10 in CD[17,18] is paralleled by an exaggerated release of this cytokine in SLE.[16] In this framework, similarly to CD, an increase of TNFa plasma levels has been described in patients with lupus nephritis and serum concentrations of soluble receptors of this cytokine show a direct correlation with the activity of SLE.[19] Moreover, the hypothesis that TNFa may be involved in the pathogenesis of SLE is supported by the findings of Yamamoto and Loskutoff, who observed in an animal model (i.e., mice with induced lupus nephritis) elevated values of this cytokine in the plasma and a widespread increased distribution of its specific mRNA, which was found in the kidney as well as in other organs such as liver and heart.[20]
120037721_IPH_26_00_R2_041504
Lupus Nephritis After Infliximab Treatment for Crohn’s Disease
5
127 128 129 130 131 132 133 134 135 136 137 138 139 140
Nevertheless, it is known that Infliximab administration may induce, in less than 1% of cases, symptoms of SLE which may resolve after discontinuation of the drug[21,22] and this evidence should be taken into consideration among possible side effects. Despite some obscure aspects, our case report suggests that the series of CD associated complaints could include a wide range of autoimmune disorders besides those which have been conventionally considered until now. Therefore, a more accurate detection of autoimmune diseases could be suggested in the diagnostic program to be performed in the course of CD. Another conclusive remark concerns the possibility that Infliximab field of appliance could be enlarged in next future even if this process will need a well-stated definition of specific indications as well as an accurate caution due to the possibility of serious adverse effects such as lymphomas,[23] opportunistic infections (including TBC)[24] and demyelinising diseases.[25]
141
REFERENCES
142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169
1.
2.
3.
4.
5.
6.
7.
8. 9.
Bernstein, C.; Blanchard, J.F.; Rawsthorne, P.; Yu, N. The prevalence of extraintestinal disease in inflammatory bowel disease: a population-based study. Am. J. Gastroenterol. 2001, 96, 1116. Toulemonde, P.; Arlic, L.; Vallee, F.; Selves, J.; Duffaut, M. Association of disseminated lupus erythematosus and Crohn’s disease. Rev. Int. Med. 2001, 22, 385. Chebli, J.M.; Gaburri, P.D.; de Souza, A.F.; Dias, K.V.; Cimino, K.O.; de CarvalhoFilho, R.J.; Lucca, F.A. Fatal evolution of systemic lupus erythematosus associated with Crohn’s disease. Arq. Gastroenterol. 2000, 37, 224. Shimizu, T.; Nishinarita, S.; Son, K.; Tomita, Y.; Yoshihiro; Matsukawa; Kitamura, N.; Horie, T.; Baba, M.; Hiranuma, M. Crohn’s disease with the onset resembling systemic lupus erythematosus. Nihon Rinsho Meneki Gakkai Kaishi 1999, 22, 164. Nishida, Y.; Murase, K.; Ashida, R.; Sasaki, O.; Ozono, Y.; Mizuta, Y.; Takeshima, F.; Makiyama, K.; Kohno, S. Familial Crohn’s disease with systemic lupus erythematosus. Am. J. Gastroenterol. 1998, 93, 2599. Sugimoto, M.; Sato, Y.; Kumagai, Y.; Suenaga, M.; Hashimoto, H.; Hirose, S. A case of systemic lupus erythematosus with lupus nephritis occurring in Crohn’s disease. Nippon Naika Gakkai Zasshi 1989, 78, 583. Van den Bosch, F.; Kruithof, E.; De Vos, M.; De Keyser, F.; Mielants, H.l. Crohn’s disease associated with spondyloarthropathy: effect of TNFa blockade with Infliximab on articular symptoms. Lancet 2000, 25, 1821. Tromm, A.; May, D.; Almus, E.; Voigt, E.; Greving, I.; Schwegler, U.; Griga, T. Cutaneous manifestations in inflammatory. Z. Gastroenterol. 2001, 39, 137. Amati, L.; Caradonna, L.; Magrone, T.; Manghisi, C.; Leandro, G.; Caccavo, D.; Covelli, V.; Sciorsci, R.L.; Minoia, P.; Jirillo, E. In vitro effects of naloxone on T-lymphocyte-dependent antibacterial activity in hepatitis C virus (HCV) infected patients and in inflammatory bowel disease (IBD) patients. Immunopharmacol. Immunotoxicol. 2001, 23, 1.
120037721_IPH_26_00_R2_041504
6 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21. 22. 23.
24. 25.
Principi et al.
Maeda, M.; Watanabe, N.; Neda, H.; Yamauchi, N.; Okamoto, T.; Sasaki, H.; Tsuji, Y.; Akiyama, S.; Tsuji, N.; Niitsu, Y. Serum tumor necrosis factor activity in inflammatory bowel disease. Immunopharmacol. Immunotoxicol. 1992, 14, 451. Caradonna, A.L.; Amati, L.; Lella, P.; Fiorillo, E.; Caccavo, D. Phagocytosis, killing, lymphocyte-mediated antibacterial activity, serum autoantibodies and plasma endotoxins in inflammatory bowel diseases. Am. J. Gastroenterol. 2000, 95, 1495. Baert, F.J.; D’Haens, G.R.; Peeters, M.; Hiele, M.I.; Schaible, T.F.; Shealy, D.; Geboes, K.; Rutgeerts, P.J. Tumor necrosis factor alpha antibody (Infliximab) therapy profoundly downregulates the inflammation in Crohn’s ileocolitis. Gastroenterolgy 1999, 116, 22. Arnott, I.D.; McDonald, D.; Williams, A.; Ghosh, S. Clinical use of Infliximab in Crohn’s disease: the Edinburgh experience. Aliment. Pharmacol. Ther. 2001, 15, 1639. Braun, J.; Brandt, J.; Listing, J.; Zink, A.; Alten, R.; Golder, W.; Gromnica-Ihle, E.; Kellner, H.; Krause, A.; Schneider, M.; Sorensen, H.; Zeidller, H.; Thriene, W.; Sieper, J. Treatment of active anckylosing spondylitis with Infliximab: a randomised controlled multicentre trial. Lancet 2002, 359, 1187. Shearn, M.A.; Hopper, J., Jr.; Biava, C.G. Membranous lupus nephropathy initially seen as idiopathic membranous nephropathy. Possible diagnostic value of tubular reticular structures. Arch. Intern. Med. 1980, 140, 1521. Tfoyos, G.C.; Nambiar, M.P.; Tenbroly, Y.; Juang, I.T. Rewiring the T-cell: signalling defects d novel prospects for the treatment of SLE. Immunology 2003, 24, 259. Niessner, M.; Volk, B.A. Altered Th1/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction (R-PCR). Clin. Exp. Immunol. 1995, 101, 28. Van Deventer, S.J.H.; Elson, C.O.; Fedorack, R.N. Multiple dose of intavenous interleukin-10 in steroid-refractory Crohn’s disease. Gastroenterology 1997, 113, 383. Tesar, V.; Irsa, M., Jr.; Zima, T.; Kalousova, M.; Bartunkove, J.; Stejaskalova, A.; Dostal, C.; Zabka, J. Soluble cytokina receptors in renal vasculitis and lupus nephritis. Med. Sci. Monit. 2002, 8, 24. Yamamoto, K.; Loskutoff, D. Expression of trasforming growth factor-b and tumour necrosis factor-a in the plasma and tissues of mice with lupus nephritis. Lab. Invest. 2000, 80, 1561. Schaible, T.F. Treatment of inflammatory diseases: safety and long term use of Infliximab. Presse Med. 2001, 30, 610. Ali, Y.; Shah, S. Infliximab-induced systemic lupus erythematosus. Ann. Intern. Med. 2001, 137, 625. Brown, S.L.; Greene, M.H.; Gershon, S.K.; Edwards, E.T.; Braun, M.M. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum. 2002, 46, 3151. Long, R.; Gardam, M. Tumour necrosis factor-alpha inhibitors and the reactivation of latent tuberculosis infection. CMAJ, Can. Med. Assoc. J. 2003, 168, 1153. Kashyap, A.S.; Kashyap, S. Infliximab-induced aseptic meningitis. Lancet 2002, 359, 1252.
Marcel Dekker, Inc.
ARTICLE/CHAPTER INFO SHEET
Product information:
IPH 26 0 0892-3973 1532-2513 120037721 Lupus Nephritis Improvement After Anti-tumour Necrosis Factor Alpha Monoclonal Antibody (Infliximab) Treatment for Crohn's Disease: A Case Report
Article information:
AUTHOR INFORMATION:
Affiliation(s) at time of authorship
Affiliation(s) at time of authorship
D/Journal: D/Volume: D/Issue: C/ISSN/ISBN: Print C/ISSN/ISBN: Web D/Article ID number: C/Article title:
D/Unarticle or Article type: C;A/Key words: D/Copyright holder: C/Author number: C/Author first name: C;A/Author middle initial: C:A/Author last name: A/Suffix to last name: C;A/Degrees: C;A/Author e-mail address: C;A/Author fax: C;A/Author phone: C;A/Title C;A/Department C;A/Institution C;A/Street Address C;A/City C;A/State/Province C;A/Postal code C;A/Country
C;A/Title C;A/Department C;A/Institution C;A/Street Address C;A/City C;A/State/Province C;A/Postal code C;A/Country C;A/Title Current C;A/Department affiliation(s): Repeat if same as C;A/Institution affiliation at time C;A/Street address C;A/City of authorship C;A/State/Province C;A/Postal code C;A/Country Mailing address: C;A/Department C;A/Institution/Company
Lupus nephritis, Infliximab, Crohn's disease, Steroids MDI 9 Enzo Ierardi M.D.
[email protected] + 39-(0)-881-747884 + 39-(0)-881-733848-9
Gastroenterology Section, Department of Medical and Occupational Sciences University of Foggia MISSING DATA S/B QUERIED TO THE CONTACT AUTHOR MISSING DATA S/B QUERIED TO THE CONTACT AUTHOR Foggia Italy
Cattedra di Gastroenterologia Università di Foggia c/o Ospedali Riuniti, Viale L. Pinto Foggia FG 71100 Italy Gastroenterology Section, Department of Medical and Occupational Sciences University of Foggia
Foggia Italy Gastroenterology Section, Department of Medical and Occupational Sciences University of Foggia
Recipient of R1 proofs: Article data:
C;A/Street address C;A/ Office complex C;A/ Suite, floor, room no. C;A/ City C;A/ Region C;A/ State/Province C;A/ Postal code C;A/ Country C/Author number: D/e-mail to receive proofs: D/Fax to receive proof: D/Submission date: D/Reviewed date: D/Revision date: D/Accepted date: D/Pub date print: D/Pub date web:
Foggia Italy 9
[email protected] + 39-(0)-881-747884
