Distinct Responses of Interleukin-6 and Other Laboratory Parameters to Treatment in a Patient with Polyarteritis Nodosa—A Case Report
Hajime Nakahama, M.D. Mitsunori Okada, M.D. Mutsuo Miyazaki, M.D. Nobuyuki Imai, M.D. Tomoko Yokokawa, M.D. and Shujiro Kubori, M.D.
HYOGO, JAPAN
Abstract The authors describe a patient in whom the serum levels of interleukin-6 (IL-6) and other laboratory parameters were monitored. The IL-6 and C-reactive protein (CRP) levels, which were extremely high before treatment, declined rapidly with administration of prednisolone. Rheumatoid factor, IgG, and platelets count declined more gradually. Thus, determination of the serum IL-6 level might be useful in diagnosing and monitoring polyarteritis nodosa. Introduction
Polyarteritis nodosa (PAN) is a relatively rare systemic vasculitic disease usually associated with poor prognosis.’ Protean manifestations of the disease reflect the diversity of the sites of vessel involvement. Whereas almost all organs can be affected, the kidney is one of the most frequently involved structures, and acute renal failure is commonly encountered. Currently the most widely employed therapy for PAN with major organ involvement consists of daily doses of oral corticosteroids (prednisone 60-100 mg) and oral cyclophosphamide (2 mg/kg).2 Intravenous pulse cyclophosphamide therapy has recently been introduced as a therapeutic alternative.’ In the present report, we describe a patient with PAN who was treated with both oral prednisolone and intravenous pulse cyclophosphamide. The effects of the therapy on the laboratory parameters that are considered to reflect the disease activity are discussed. -.
From the
Department
of Medicine, Kansai Rosai
-.-
-
-.
--
-
Hospital, Hyogo, Japan
512
-
-
-
-
.
-
-
--
-
513 Case
Report The patient, a sixty-five-year-old man, was hospitalized in September, 1990, with a onemonth history of fever, chills, and headache. He reported experiencing anorexia and general fatigue for a few months. Upon physical examination, his blood pressure was 150/82 mmHg. High spiked fever ( > 38.5°C) appeared once or twice every day. Examination of the patient’s chest, abdomen, neurological status, skin, and joints revealed normal findings. The initial laboratory evaluation demonstrated the following values: hemoglobin 10.0 mg/dL, leukocytes gooo/MM3, platelets 53.4 x 104/mm3; serum creatinine 1.1 mg/dL, blood urea nitrogen (BUN) 23.4 mg/dL; 4-6 urinary red blood cells and 10-20 white blood cells per high-power field and coarse granular urinary casts. The chest x-ray examination appeared normal. Abdominal computed tomography (CT) and echography were nonspecific except for a small cyst in the left kidney. The patient was treated empirically with antibiotics and the presumptive diagnosis was abscess in an unidentified organ. Further laboratory studies revealed elevated C-reactive protein (CRP) (14.9 mg/dL), rheumatoid factor (RF) (197 IU/mL), interleukin-6 (IL-6) (122 pg/mL), and immunoglobulin G (IgG) (2130 mg/dL). IL-6 was determined by an enzyme-linked immunosorbent assay (ELISA) as previously reported.4 Antinuclear antibody was positive. Anti-DNA antibody, hepatitis B serology, antineutophil cytoplasmic antibody (ANCA), cryoglobulin, and circulating immune complexes were negative. During the course of antibiotic treatment for ten days, the patient’s renal function deteriorated acutely. Serum creatinine and BUN were elevated to 5.6 mg/dL and 40.6 mg/dL, respectively. A gallium scan revealed intense uptake in the bilateral renal parenchyma. An ultrasound-guided percutaneous renal biopsy was performed. Histologic findings were typical of PAN with the muscular renal arteries exhibiting fibrinoid necrosis and a marked reduction by inflammation of the vessel lumen. The glomeruli were almost intact except for a few that had hypercellularity, segmental necrosis, and crescents. Interstitial leukocytes infiltration was also present.
Prednisolone, 80 mg/day,
was administered intravenously for nine consecutive days, fol60 lowed by prednisolone, mg/day. The fever and headache subsided immediately with the prednisolone medication. The patient was then given intravenous cyclophosphamide (1 g) at day 16 after initiation of prednisolone therapy. IL-6, CRP, RF, IgG, leukocytes count, and platelets count were employed as markers of disease activity and were subsequently monitored. Temporal data on these parameters are shown in Figure 1. Prednisolone induced a rapid fall in IL-6 and CRP, which was followed by a small fluctuation of the IL-6 level. On the other hand, RF, IgG, and platelet count declined more gradually and at no point showed an abrupt fall. The leukocytes count increased with prednisolone and then decreased rapidly with cy-
oral
clophosphamide. Renal failure creatinine of 4.3
irreversible despite the intensive mg/dL and a BUN of 46.0 mg/dL. was
therapeutic
measures, with
a serum
Discussion
Polyarteritis
nodosa exhibits
a
variable
complex
of fever,
weight loss, anemia, arthritis,
514
Fic. 1. The effect of prednisolone
and
cyclophosphamide on laboratory a sixty-five-year-old male patient with polyarteritis noparameters in dosa.
dermatitis, myopathy, neuropathy, and gastrointestinal renal disease. However, the diagnosis of PAN solely by clinical and laboratory findings is difficult. The recognition of vasculitic lesions with supportive evidence derived from radiologic or pathologic studies, or both, is mandatory. Renal biopsy is often indicated and is probably the most informative measure of the efficacy of treatment. Some laboratory parameters, which by themselves are not conclusive, reflect disease activity and are employed for follow-up monitoring of the disease. At present, CRP is the simplest, albeit not specific, parameter, together with measurement of the erythrocyte sedimentation rate. Reliable and specific serologic markers of PAN have not yet been established. The experience from our patient indicates IL-6 to be a new and valuable parameter in the diagnosing and monitoring of PAN. Interleukin-65 is a multifunctional protein produced by a variety of cell types, including T lymphocytes, monocytes, diploid fibroblasts, hepatocytes, cardiac myxomas, cervical and bladder cell carcinomas, vascular endothelial cells, and human myelomas. Its function in vivo is currently not fully understood, but many in vitro functions have been reported. These include stimulation of the differentiation of cytotoxic T cells in concert with IL-2 or interferon (IFN) gamma,6 stimulation of production of acute-phase proteins by hepatocytes,’ and stimula-
515 tion of differentiation and antibody production by B lymphocytes. Generally, in vivo, serum 9 levels of IL-6 increase in response to injury and at an early stage of the acute-phase responses.9 Diseases or conditions associated with raised serum IL-6 levels include Castleman’s disease,’° cardiac myxomas,&dquo; severe burns,’2 acute rejection episodes in renal transplant patients,&dquo; and rheumatoid arthritis.’4 All of these are characterized by fever, an increase in the serum levels of acute-phase proteins, and, occasionally, hypergammaglobulinemia. Recently, IL-6 has been shown to promote maturation of megakaryocytes and to increase blood platelets.&dquo; In our patient, the serum IL-6 level before treatment was extremely high compared with the serum levels determined by the same method in 3 patients with chronic renal failure due to chronic glumerulonephritis ( 11.0, 12.9, and 13.2 pg/mL, respectively). It is conceivable that the elevated IL-6 level was responsible for thrombocytosis found in our patient. As indicated, IL-6 declined rapidly with prednisolone, as did CRP, suggesting a close link between these two proteins. Since other, more frequently employed laboratory parameters responded more gradually to the treatment, IL-6 seems to be a more sensitive parameter for monitoring the disease activity of PAN.
Conclusion Determination of the serum IL-6 level might be useful in diagnosing and monitoring PAN. It remains to be elucidated whether a high IL-6 level is the cause or the result-or both-of PAN.
Acknowledgment We wish to thank Drs. M. Fujibayashi, T. Matsuda, and M. Fukunaga of Osaka University Medical School for their expert technical assistance in measuring IL-6.
Hajime Nakahama, M. D. Department of Medicine Kansai Rosai Hospital Inabaso 3-1-69 Amagasaki Hyogo 660, Japan
References 1. Kurland LT, Chuang TY, Hunder GG: The epidemiology of systemic arteritis. In: Current Topics in Rheumatology : Epidemiology of the Rheumatic Disease. ed. by Laurence RE, Shulman LE. New York: Gower Medical, 1984. 2. Wolff SM: Polyarteritis nodosa group. In: Cecil Textbook of Medicine, ed. by Wyngaarden JB, Smith LH Jr. Philadelphia: WB Saunders Company, 1988, pp. 2028-2030. 3. Fort JG, Abruzzo JL: Reversal of progressive necrotizing vasculitis with intravenous pulse cyclophosphamide and methylprednisolone. Arthritis Rheum 31:1194-1198 1988.
T, Hirano T, Kishimoto T: Establishment of interleukin (IL6)/B cell stimulatory factor 2-dependent cell line and preparation of anti-IL6 monoclonal antibodies. Eur J Immunol 18:651-956, 1988. 5. Hirano T, Yasukawa K, Harada H, et al: Complementary DNA for a novel human interleukin (BSF-2) that induces B lyphocytes to produce immunoglobulin. Nature 324:73-76, 1980. 6. Lotz M, Jirik F, Kaboridis R, et al: BSF-2/IL-6 is a costimulant for human thymocytes and T lymphocytes. J Exp Med 167:1253-1256, 1988. 7. Gauldie J, Richards C, Harnigh D, et al: Interferon beta-2/B-cell stimulatory factor type 2 shares identity
4. Matsuda an
516
8.
9.
10.
11.
with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein in liver cells. Proc Natl Acad Sci USA 84:7251-7255, 1987. Koshimoto T, Hirano T: Molecular regulation of B lymphocyte response. Ann Rev Immunol 6:485-512, 1988. Nishimoto N, Yoshizaki K, Tagoh H, et al: Elevation of serum interleukin-6 prior to acute phase proteins on the inflammation by surgical operation. Clin Immunol Immunopathol 50:399-401, 1989. Yoshizaki K, Matsuda T, Nishimoto N, et al: Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease. Blood 74:1360-1367, 1989. Hirano T, Tata T, Yasukawa K, et al: Human B-cell differentiation factor defined by an anti-peptide antibody and its possible role in antibody production. Proc
84:228-231, 1987. Nijsten MWN, Degroot ER, TenDuis HJ,
Natl Acad Sci USA 12.
levels of interleukin-6 and acute cet 2:921, 1987.
et al:
Serum Lan-
phase responses.
13. Van Oers MHJ, Van Der Heyden AAPAM, Aarden LA: Interleukin-6 (IL-6) in serum and urine of renal transplant recipients. Clin Exp Immunol 71:314-319, 1988. 14. Hirano T, Matsuda T, Turner M, et al: Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 18:1797-1801, 1988. 15. Asano S, Okano A, Ozawa K, et al: In vivo effects of recombinant interleukin-6 in primates: Stimulated production of platelets. Blood 75:1602-1605, 1990.
Hajime Nakahama, M.D. Mitsunori Okada, M.D. Mutsuo Miyazaki, M.D. Nobuyuki Imai, M.D. Tomoko Yokokawa, M.D. and Shujiro Kubori, M.D.
HYOGO, JAPAN
Abstract The authors describe a patient in whom the serum levels of interleukin-6 (IL-6) and other laboratory parameters were monitored. The IL-6 and C-reactive protein (CRP) levels, which were extremely high before treatment, declined rapidly with administration of prednisolone. Rheumatoid factor, IgG, and platelets count declined more gradually. Thus, determination of the serum IL-6 level might be useful in diagnosing and monitoring polyarteritis nodosa. Introduction
Polyarteritis nodosa (PAN) is a relatively rare systemic vasculitic disease usually associated with poor prognosis.’ Protean manifestations of the disease reflect the diversity of the sites of vessel involvement. Whereas almost all organs can be affected, the kidney is one of the most frequently involved structures, and acute renal failure is commonly encountered. Currently the most widely employed therapy for PAN with major organ involvement consists of daily doses of oral corticosteroids (prednisone 60-100 mg) and oral cyclophosphamide (2 mg/kg).2 Intravenous pulse cyclophosphamide therapy has recently been introduced as a therapeutic alternative.’ In the present report, we describe a patient with PAN who was treated with both oral prednisolone and intravenous pulse cyclophosphamide. The effects of the therapy on the laboratory parameters that are considered to reflect the disease activity are discussed. -.
From the
Department
of Medicine, Kansai Rosai
-.-
-
-.
--
-
Hospital, Hyogo, Japan
512
-
-
-
-
.
-
-
--
-
513 Case
Report The patient, a sixty-five-year-old man, was hospitalized in September, 1990, with a onemonth history of fever, chills, and headache. He reported experiencing anorexia and general fatigue for a few months. Upon physical examination, his blood pressure was 150/82 mmHg. High spiked fever ( > 38.5°C) appeared once or twice every day. Examination of the patient’s chest, abdomen, neurological status, skin, and joints revealed normal findings. The initial laboratory evaluation demonstrated the following values: hemoglobin 10.0 mg/dL, leukocytes gooo/MM3, platelets 53.4 x 104/mm3; serum creatinine 1.1 mg/dL, blood urea nitrogen (BUN) 23.4 mg/dL; 4-6 urinary red blood cells and 10-20 white blood cells per high-power field and coarse granular urinary casts. The chest x-ray examination appeared normal. Abdominal computed tomography (CT) and echography were nonspecific except for a small cyst in the left kidney. The patient was treated empirically with antibiotics and the presumptive diagnosis was abscess in an unidentified organ. Further laboratory studies revealed elevated C-reactive protein (CRP) (14.9 mg/dL), rheumatoid factor (RF) (197 IU/mL), interleukin-6 (IL-6) (122 pg/mL), and immunoglobulin G (IgG) (2130 mg/dL). IL-6 was determined by an enzyme-linked immunosorbent assay (ELISA) as previously reported.4 Antinuclear antibody was positive. Anti-DNA antibody, hepatitis B serology, antineutophil cytoplasmic antibody (ANCA), cryoglobulin, and circulating immune complexes were negative. During the course of antibiotic treatment for ten days, the patient’s renal function deteriorated acutely. Serum creatinine and BUN were elevated to 5.6 mg/dL and 40.6 mg/dL, respectively. A gallium scan revealed intense uptake in the bilateral renal parenchyma. An ultrasound-guided percutaneous renal biopsy was performed. Histologic findings were typical of PAN with the muscular renal arteries exhibiting fibrinoid necrosis and a marked reduction by inflammation of the vessel lumen. The glomeruli were almost intact except for a few that had hypercellularity, segmental necrosis, and crescents. Interstitial leukocytes infiltration was also present.
Prednisolone, 80 mg/day,
was administered intravenously for nine consecutive days, fol60 lowed by prednisolone, mg/day. The fever and headache subsided immediately with the prednisolone medication. The patient was then given intravenous cyclophosphamide (1 g) at day 16 after initiation of prednisolone therapy. IL-6, CRP, RF, IgG, leukocytes count, and platelets count were employed as markers of disease activity and were subsequently monitored. Temporal data on these parameters are shown in Figure 1. Prednisolone induced a rapid fall in IL-6 and CRP, which was followed by a small fluctuation of the IL-6 level. On the other hand, RF, IgG, and platelet count declined more gradually and at no point showed an abrupt fall. The leukocytes count increased with prednisolone and then decreased rapidly with cy-
oral
clophosphamide. Renal failure creatinine of 4.3
irreversible despite the intensive mg/dL and a BUN of 46.0 mg/dL. was
therapeutic
measures, with
a serum
Discussion
Polyarteritis
nodosa exhibits
a
variable
complex
of fever,
weight loss, anemia, arthritis,
514
Fic. 1. The effect of prednisolone
and
cyclophosphamide on laboratory a sixty-five-year-old male patient with polyarteritis noparameters in dosa.
dermatitis, myopathy, neuropathy, and gastrointestinal renal disease. However, the diagnosis of PAN solely by clinical and laboratory findings is difficult. The recognition of vasculitic lesions with supportive evidence derived from radiologic or pathologic studies, or both, is mandatory. Renal biopsy is often indicated and is probably the most informative measure of the efficacy of treatment. Some laboratory parameters, which by themselves are not conclusive, reflect disease activity and are employed for follow-up monitoring of the disease. At present, CRP is the simplest, albeit not specific, parameter, together with measurement of the erythrocyte sedimentation rate. Reliable and specific serologic markers of PAN have not yet been established. The experience from our patient indicates IL-6 to be a new and valuable parameter in the diagnosing and monitoring of PAN. Interleukin-65 is a multifunctional protein produced by a variety of cell types, including T lymphocytes, monocytes, diploid fibroblasts, hepatocytes, cardiac myxomas, cervical and bladder cell carcinomas, vascular endothelial cells, and human myelomas. Its function in vivo is currently not fully understood, but many in vitro functions have been reported. These include stimulation of the differentiation of cytotoxic T cells in concert with IL-2 or interferon (IFN) gamma,6 stimulation of production of acute-phase proteins by hepatocytes,’ and stimula-
515 tion of differentiation and antibody production by B lymphocytes. Generally, in vivo, serum 9 levels of IL-6 increase in response to injury and at an early stage of the acute-phase responses.9 Diseases or conditions associated with raised serum IL-6 levels include Castleman’s disease,’° cardiac myxomas,&dquo; severe burns,’2 acute rejection episodes in renal transplant patients,&dquo; and rheumatoid arthritis.’4 All of these are characterized by fever, an increase in the serum levels of acute-phase proteins, and, occasionally, hypergammaglobulinemia. Recently, IL-6 has been shown to promote maturation of megakaryocytes and to increase blood platelets.&dquo; In our patient, the serum IL-6 level before treatment was extremely high compared with the serum levels determined by the same method in 3 patients with chronic renal failure due to chronic glumerulonephritis ( 11.0, 12.9, and 13.2 pg/mL, respectively). It is conceivable that the elevated IL-6 level was responsible for thrombocytosis found in our patient. As indicated, IL-6 declined rapidly with prednisolone, as did CRP, suggesting a close link between these two proteins. Since other, more frequently employed laboratory parameters responded more gradually to the treatment, IL-6 seems to be a more sensitive parameter for monitoring the disease activity of PAN.
Conclusion Determination of the serum IL-6 level might be useful in diagnosing and monitoring PAN. It remains to be elucidated whether a high IL-6 level is the cause or the result-or both-of PAN.
Acknowledgment We wish to thank Drs. M. Fujibayashi, T. Matsuda, and M. Fukunaga of Osaka University Medical School for their expert technical assistance in measuring IL-6.
Hajime Nakahama, M. D. Department of Medicine Kansai Rosai Hospital Inabaso 3-1-69 Amagasaki Hyogo 660, Japan
References 1. Kurland LT, Chuang TY, Hunder GG: The epidemiology of systemic arteritis. In: Current Topics in Rheumatology : Epidemiology of the Rheumatic Disease. ed. by Laurence RE, Shulman LE. New York: Gower Medical, 1984. 2. Wolff SM: Polyarteritis nodosa group. In: Cecil Textbook of Medicine, ed. by Wyngaarden JB, Smith LH Jr. Philadelphia: WB Saunders Company, 1988, pp. 2028-2030. 3. Fort JG, Abruzzo JL: Reversal of progressive necrotizing vasculitis with intravenous pulse cyclophosphamide and methylprednisolone. Arthritis Rheum 31:1194-1198 1988.
T, Hirano T, Kishimoto T: Establishment of interleukin (IL6)/B cell stimulatory factor 2-dependent cell line and preparation of anti-IL6 monoclonal antibodies. Eur J Immunol 18:651-956, 1988. 5. Hirano T, Yasukawa K, Harada H, et al: Complementary DNA for a novel human interleukin (BSF-2) that induces B lyphocytes to produce immunoglobulin. Nature 324:73-76, 1980. 6. Lotz M, Jirik F, Kaboridis R, et al: BSF-2/IL-6 is a costimulant for human thymocytes and T lymphocytes. J Exp Med 167:1253-1256, 1988. 7. Gauldie J, Richards C, Harnigh D, et al: Interferon beta-2/B-cell stimulatory factor type 2 shares identity
4. Matsuda an
516
8.
9.
10.
11.
with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein in liver cells. Proc Natl Acad Sci USA 84:7251-7255, 1987. Koshimoto T, Hirano T: Molecular regulation of B lymphocyte response. Ann Rev Immunol 6:485-512, 1988. Nishimoto N, Yoshizaki K, Tagoh H, et al: Elevation of serum interleukin-6 prior to acute phase proteins on the inflammation by surgical operation. Clin Immunol Immunopathol 50:399-401, 1989. Yoshizaki K, Matsuda T, Nishimoto N, et al: Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman’s disease. Blood 74:1360-1367, 1989. Hirano T, Tata T, Yasukawa K, et al: Human B-cell differentiation factor defined by an anti-peptide antibody and its possible role in antibody production. Proc
84:228-231, 1987. Nijsten MWN, Degroot ER, TenDuis HJ,
Natl Acad Sci USA 12.
levels of interleukin-6 and acute cet 2:921, 1987.
et al:
Serum Lan-
phase responses.
13. Van Oers MHJ, Van Der Heyden AAPAM, Aarden LA: Interleukin-6 (IL-6) in serum and urine of renal transplant recipients. Clin Exp Immunol 71:314-319, 1988. 14. Hirano T, Matsuda T, Turner M, et al: Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 18:1797-1801, 1988. 15. Asano S, Okano A, Ozawa K, et al: In vivo effects of recombinant interleukin-6 in primates: Stimulated production of platelets. Blood 75:1602-1605, 1990.
