Denz, H.

Fuchs, D.

Hausen, A.

Huber, H.

Nachbaur, D.

Reibnegger, G.

Thaler, J.

Wachter, H.

Werner, E. R.

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Denz 1'1 al.: Urinary Neoptcrin in Monoclonal Gammopathies 107 Ptcridines Vol. 2. 1990. pp. 107 - 109 Short Communication Urinary Neopterin in Monoclonal Gammopathies H. Denzl» )), D. Fuchs21, A. Hausen"). H. Huber l), D. Nachbaur ll, G. Reibnegger"), J. Thalerl), E. R. Werner") and H . Wachter2 ) I) Klinik fur lnnere Medizin, Universitat Tnnsbruck, Anichstr. 35, A-6020 Tnnsbruck , Austria 2 ) Institut fur Medizinische Chemie und Biochemie, Universitat Innsbruck, Fritz-Pregl-Str. 3, A-6020 [nns-bruck, Austria ( Reeci ved March I 990) Introduction Multiple myeloma (MM) is a hematological disorder caused by the emergence of a malignant clone of plasma cells, a mature form of B lymphocytes. The disease is frequently preceded by a phase of mono-clonal gammopathy characterized by the presence of a paraprotein in the serum of the patients, but without signs or symptoms of illness. Since 1 - 2%!yea r of the patients with paraproteinemia develop MM, most authors use the term "monoclonal gammopathy of unknown significance" (MGUS). In order to get clinically relevant indicators for the prognosis and treatment of myeloma patients, Durie and Salmon established a staging system which cor-relates well with the estimated total number of malig-nant cells (1) . Additional factors were found to cor-relate with the prognosis, e. g .. the labeling index indicating the percentage of proliferating plasma cells in the bone marrow (2) , and the serum concentration of beta-2-microglobulin, which has been shown to be produced by myeloma cultures in vitro (3,4). D-erythro-neopterin is secreted by monocytes/mac-rophages upon stimulation with interferon gamma (5). Thi s effect can be synergistically enhanced by tumor necrosis factor alpha (6). Neopterin has been shown to be of prognostic value in Hodgkin's disease, non-Hodgkin's lymphoma and chronic myelogenous leu-kemia (7, 8). " Author to whom correspondence should be addressed. Present address: Abt. Innere Medizin, Universitiitsklinik. Petersgraben 4, CH-4031 Basel, Switzerland Plcrid ines \ '0 1. ~ No.2 Copyrighl " 1991 Walter de Gruyter' Berlin ' New York The aim of this study was to analyse the diagnostic value of urinary neopterin in patients . with MGUS and multiple myeloma. Patients and Methods PUlien lS 51 patients were included in this study. All of them had monoclonal gammopathy confirmed by immu-noelectrophoresis of serum and/or urine. 41 patients (80%) suffered from MM , 10 patients had MGUS. MM was excluded in these patients by bone marrow examination « 10% plasma cells), bone radiography (lack of osteolytic lesions) and a stable course of the myeloma-protein. Staging of MM was performed ac-cording to the sys tem of Salmon and Durie (1). Characteristics of patients are summarized in Table 1. None of the patients with MGUS was treated. Out of the patients with MM , 10/41 were evaluated at the time of diagnosis, 8/41 had no treatment because of remission or stable disease. The other 23 were under Table I . Characteristics of patients Patients Mean age (years Male: Female MGUS M yeloma Stage: 1 II III n = 51 65 (range 37 - 86) 29: 22 10 (19.6°;;,) 41 (80.4 % ) 11 6 24 lO~ chemotherapy for active disease and determination of neopterin was Llsually performed four weeks after last therapy. Analytical procedures Hemoglobin and leukocytes were routinely evaluated from fresh blood samples using a cell counter (Coul-ter, Miami, FL USA). Differential counts were done by examination of stained blood smears. Beta-2-mi-croglobulin was measured using a commercially avail-able radioimmunoassay (Pharmacia, Uppsala, Swe-den). Neopterin was determined by an optimized and fully automated high pressure liquid chromatography technique without previous oxidative treatment as described elsewhere (9). By this reverse-phase tech-nique, urinary creatinine is simultaneously determined in the same urine specimen. To account for variations of urine concentrations, neopterin levels are expressed as I1mol /mol creatinine. Statistics For the evaluation of differences between various groups of patients we used Kruskal-Wallis rank sum test. To define the strength and significance of cor-relations we computed Spearman's rank correlation coefficients. Results Neop/erin. hct{{-:2-microglobllIiJl {{nd hema/ological val-lies (Table :2) Neopterin and beta-2-microglobulin In MGUS patients the mean neopterin value was below the upper normal limit. In contrast, in MM patients the mean value was clearly elevated. Due to the high standard deviations, the difference between Denz ('I Ill.: Urinary Neoptcrin in Monoclonal Gammopathies MGUS and MM did not reach statistical significance (p = 0.119). Comparing patients with MGUS and MM stage I (mean value 199 ± 86) with patients showing M M stage II / Ill (362 ± 249) the difference was statistically significant (p = 0.(06) . Beta-2-mi-croglobulin concentrations in the serum were higher in patients with M M stage II / III than in patients with MGUS and MM stage I (p < 0.05). Hemoglobin, monocytes and peripheral lymphocytes Hemoglobin concentrations and total number of pe-ripheral lymphocytes were significantly lower in M M of advanced stage than in MGUS and stage I MM (p < 0.001 and p = 0.035 , respectively) , whereas the number of peripheral monocytes was not different (p = 0.388). Correlation hetll'ccn I1coprerin . heta-2-nzicroglobulin {lnd hematological paramerers Correlating neopterin with the other values we found a significant negative correlation between neopterin and the hemoglobin concentrations (r = -0.542, p = < 0.05). A positive correlation was seen between neopterin and the number of peripheral monocytes (r = 0.38, p < 0.05), whereas a correlation with lym -phocytes was not found. Beta-2-microglobulin cor-related with hemoglobin values in a similar manner as neopterin (r= -0.702, p= <0.01). Finally we observed a significant positive correlation between neopterin and beta-2-microglobulin (r = 0.53, p < 0.05) . Discussion Our data show elevated concentrations of urinary neopterin and beta-2-microglobulin in patients with MM, especially in patients with more advanced dis-Table 2. Urinary neopterin. beta-2-microglobulin and hematological parameters in patients with MGUS and multiple myeloma Neopterin (~llllol /mol creaL) Beta-2-microgl. (mg/L) Hemoglobin (G / l00 ML) Lymphocytes (nip l) Monocytes (l1ip l) Ptcridines Vol. 2 No.2 MGUS 200 ± 107 3. 1 ± 2.8 14.7 ± 1.1 2139 ± 575 660 ± 322 Myeloma p 318 ± 227 0. 119 8.0 ± 9.8 <0.050 11.8 ± 2.5 0.001 1363 ± 675 0.002 477 ± 339 0.132  Dt:llZ Cl (II.: Urina ry Nt:optcrin in Monoclonal Gammopathics ease. Similar results havc been described by others (10 - 12). From our data the question remains open. if neopterin is of special va lue in the differential di-agnosis between MG U S and MM. since we havc found similar values in MGUS and MM stage l. Nevertheless, increased va lues renect a significant ac-tivity of the disease and may represent an additional parameter, e. g., for the deci sio n if therapy is necessary or not. The close correlation between neopterin and beta-2-microglobulin argues in favor of a similar clinical relevance of both markers. additionally neopterin is not dependent on the renal function. since neopterin values arc related to urinary creatinine. Thomas (11 ) found that urinary neopterin concentrations correla te even stronger with the calculated tumor cell mass tha n beta-2-microglobulin . Previous results have shown a negative correlation between hemoglobin and neopterin values (13) point-ing to a potential role of immunological factors in the pathogenesis of anemia in hematological disorders . These data have been confirmed also in the present analysis of patients with \1 GU S and MM. Anemia in these patients might be not only due to bone marrow replacement. bu t mediated by a number of cytokines. e. g., interfero n gamma or tumor necrosis factor, although we found a correlation between the degree of bone marrow infi ltration by plasma cells and that of anemia (data not shown). Elevated neopterin values are a sign of activation of ccll mediated immunity. Therefore our data raise the question . whether the monocyte/ macrophage system is activated in the framework of an - ineffective -immune reaction against the tumor or whether ele-vated neopterin concentrations result from macro-phage activation by cytokines produced by the mali g-nant cells themselves . These two aspects . the clinical relevance on the one hand and the expression of an activation status of monocytes!macrophages on the other hand. ma ke neopterin an interesting marker in monoclonal gam-mopathies. 109 References I. Duric. B. G. M. & Sa lm on. S. L ( 1975) A clinical stagin g systcm for multiplc mye loma . Cancer 3(,. X42 - X54. ., Grt:ipp. P. R . & Kyk. R. A. (19X3) Clinical. mo rph o logica l. and cell kinetic diITt:n:nccs amo ng mult ipk myeloma. monoclon al ga lllill opat hy o f undertcrmincd signi lica nce. and smoldering mul t ip le myel oma. Blood 62. 166 -1 73. 3. Peest. D .. Ba rtels. 13 ._ Dallmann . I.. Seht:del. I. & Deichcr. II. ( 1986) Cy tostat ic drug sensi ti vity test fo r human Illultiple myeloma _ measurin g mo noclonal immunoglobulin pro-duced by bone marrow cclls in vitro . Canccr C hemot her. Pharmacol. 17. 69 - 76. 4. Grcipp. P. R .. Ka tzma nn . .I . A .. O·Falion. W. M. & Kyle. R. A. (19XX) Val ue of ~ ~-microglobulin lcvel and plasma cell labeling indiccs as prognostic factors in patient s with ncwly diagnosed myc loma. Blood 72. 219 - 223 . 5. Huber. C, Batchelor . .I. R., Fuchs, D .. Ha usen. 1\ .. Lang. A .. N iederwieser, D .. Reibneggc r. G .. Swctl y, P .. Tro ppma ir . .I. & Wachtn. H . (1984) Imillunc rcsponsc-associated pro-duction of ncop tcri n. Rclcasc from macrophagcs primarily under co ntrol of interferon ga mma . .I. Exp. Med. 160 . 310 -316. 6. Werner-Felmayer. G .. Werner, E. R .. Fuchs. D .. Ha uscn. 1\ .. Reibnegger. G. & Wachter, H. (19X9) Tumo r nccrosis fa ctor alpha and lipopolysaccharide enhance interfero n in-duced tryptoph an degradation and pteridine synthesis in human cells. BioI. C hem . lIoppe Seyler 370. 1063 - 1069. 7. Abate. G. , Comella , P .. Marfe lla . A .. Santelli. G. , Nitsch, r: .. Fiorc, M. & Perna . M. (1989) Prognostic relcva nct: of urinary neo pt erin non-H odgk in's lymphomas. Cancer 63. 4X4-489. 8. Denz. H . A .. Fuchs. D. , Grunewald , K. , Hausen_ A .. Huber. II.. Thalcr. .I .. Reibneggcr. G .. Wcrner. E. R . & Wachtcr. H . (1989) U rin a ry neopleri n as a prognoslic fac tor in hac-mato logica l neoplasias. Pteridines I. 167 -1 70. 9. Wachter. H .. fuchs , D .. Hauscn. A .. Rcibncggcr. G. & Werner. E. R. (1 989) Ncopterin as markcr for act iva ti on of cellular immunity: Immunological basis and clinical appli-cation. Ad v. Cl in . C hem. 27. 8 1- 141. 10. Ha ust:n, A., Fuchs. D .. Grunewald, K., Huber, H. , Kon ig, K . & Wachtcr. H . (1982) Urinary neoptcrin in thc assess-mcnt of lympho id and myeloid neoplasia , and neopterinc levels in haem olytic a naemia a nd benign mon oclonal ga m-mopathy. Clin. Biochcm . 15. 34-37. II . Thomas. r .. Mura. P .. Ta ll inea u. C. Bo unaud. M. P .. Reiss . D . & Bontoux. D . (1985) Intcrct du dosage de la ncopterinc urinai re dans Ic myc lomc mult iplc. Rcv. du R hUlllatismc 52. 381 - 383. 12. Fine . .I .-M .. Lambin . P. & Desjobert , H. (1988) Se rum neopterin a nd [3~-microglobulin concentrations in mono-clonal gammopathies. Acta Med. Scand. 224, 179 - 182. 13 _ Dcnz. H., Fuchs . D .. Hubcr, H .. Nachbaur_ D., Rcibncgger. G .. Thaler . .I .• Werner. E. R . & Wachter, H. (1990) Corre-lation bctwecn ncoptcrin . intcrfcron-gamma and haemo-globin in patient s with haematological disorders. Eur. .I . Haematol. 44: 186 -1 89. Ptcridines Vo l. 2 :\ l) . 2 

Urinary Neopterin in Monoclonal Gammopathies

Urinary Neopterin in Monoclonal Gammopathies

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