SERUM C-REACTIVE PROTEIN IN POLYMYALGIA RHEUMATICA

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1 SERUM C-REACTIVE ROTEIN IN OLYMYALGIA RHEUMATICA A rospective Serial Study R. K. MALLYA, C. R. K. HIND, H. BERRY, and M. B. EYS A prospective serial study of 13 well-documented, previously untreated cases of polymyalgia rheumatica was undertaken in order to assess the behavior of the nonspecific indices of disease activity, erythrocyte sedimentation rate and serum C-reactive protein (CR) concentration, during induction of disease remission by prednisolone therapy. The clinical manifestations of all patients responded rapidly and completely to steroids, and the serum CR value, which was raised in all patients at presentation, fell to normal at a rate which precisely reflected the clinical improvement. The erythrocyte sedimentation rate also fell, but did so much more slowly than the CR concentration and, in half the patients, was still not normal after 14 days. These results indicate that assay of serum CR provides a precise means of objectively assessing the course of ~~ ~ From the Department of Rheumatology, King s College Hospital, London, and the MRC Acute hase rotein Research Group, Immunological Medicine Unit, Department of Medicine, Royal ostgraduate Medical School, London, United Kingdom. Supported in part by Medical Research Council rogramme grant ( to rofessor epys. Dr. Hind is a Medical Research Council Training Fellow. R. K. Mallya, MB. MRC: Senior Registrar ip Rheumatology, Department of Rheumatology, King s College Hospital (current address: Department of Rheumatology, Guy s Hospital, St. rhomas s Street, London, SEI); C. R. K. Hind, BSc (Hons), MB, MRC: Research Fellow and Honorary Senior Registrar, MRC Acute hase rotein Research Group, Immunological Medicine Unit, Department of Medicine, Royal ostgraduate Medical School; H. Berry, DM, MRC: Consultant Rheumatologist, Department of Rheumatology, King s College Hospital; M. B. epys, MD, hd, FRC: rofessor of Immunological Medicine, MRC Acute hase rotein Research Group, Immunological Medicine Unit, Department of Medicine, Royal ostgraduate Medical School. Address reprint requests to rof. M. B. epys, Department of Medicine, Royal ostgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 OHS, England. Submitted for publication June 13, 1984; accepted in revised form October 3, polymyalgia rheumatica during initial therapy with steroids, and suggest that routine measurements of CR may make a useful contribution to the management of the disease. olymyalgia rheumatica (MR) is a common disorder of the elderly, characterized by symmetric pain and stiffness affecting the proximal muscles of the limbs and torso (1,2). Giant cell arteritis (temporal arteritis), with its associated high risk of eye involvement, may occur in association with MR, the incidence having been shown to be between 6% (3) and 50% (4), but it also occurs without MR. The etiology and pathogenesis of these syndromes are not known, although, together with the clinical findings, serologic abnormalities indicative of active inflammation are almost always present. These abnormalities include an elevated erythrocyte sedimentation rate (ESR) in most, but not all, cases (5,6) and increased concentrations of various acute-phase plasma proteins (7,8) and of liver enzymes such as alkaline phosphatase and y- glutamyl transferase (9). These nonspecific abnormalities provide diagnostic evidence; the ESR has been widely used for this purpose and for monitoring the patient s response to therapy. Treatment with oral prednisolone is effective in all cases, and progress is usually very rapid, provided a sufficient dose is given (10). In patients with temporal arteritis, this form of prompt intervention is mandatory in order to minimize the risk of loss of sight. Although previous studies have established the correlation at presentation between disease activity and objective indices such as ESR and serum C- reactive protein (CR) (7,8), and have demonstrated normalization once clinical remission has been in- Arthritis and Rheumatism, Vol. 28, No. 4 (April 1985)

2 384 MALLYA ET AL duced, the relative rates of response of these variables during induction of remission have not previously been precisely monitored. We report here a prospective serial study in which patients with MR were evaluated clinically in detail, and their levels of ESR, serum CR, and hepatic enzymes were monitored at frequent intervals after starting prednisolone therapy. Our results indicate that serum CR responds much more rapidly than the ESR and, furthermore, it returns to normal by day 7-14 in almost all cases. This information provides a framework for using the CR measurement on a real-time basis in the objective assessment and management of MR. ATIENTS AND METHODS Thirteen patients (12 women and 1 man) with a mean age of 67 years (range 58-82), who presented to the rheumatology clinics at King s College and Lewisham Hospitals during a 6-month period, were included in the study. The diagnosis of MR was made on the basis of established criteria (7,l I), including the complaint of severe proximal upper limb stiffness and pain lasting for an hour or more each morning. The mean duration of symptoms at presentation was 9.3 months (range 6-18 months), and none of the patients had received any medication before the diagnosis was made. Two patients who also had pain and tenderness over the temporal artery, which was associated with blurring of vision, underwent temporal artery biopsy; the sample from only 1 of these patients showed giant cell arteritis. It was not considered justifiable or necessary to perform biopsies on the remaining patients who had typical MR. atients who had MR without proven temporal arteritis were given prednisolone at a dosage of 15 mg/day for 1 week and 10 mglday for the second week. The dosage was subsequently reduced by 1 mg/day/week to reach the lowest dosage capable of maintaining clinical remission. atients with temporal arteritis were given prednisolone at a dosage of 60 mg/day for 1 week and 50 mg/day for the second week. Subsequently, the dosage was reduced by 5 mgidayl week until the lowest dosage able to maintain clinical remission was achieved. All these patients remained in complete clinical remission for at least the next 12 months. All patients were assessed clinically on days 0 (initial presentation), 3, 7, and 14 by the same observer (RKM). Samples of venous blood were obtained at the time of clinical assessment and were drawn at approximately the same time each day to minimize the possibility of diurnal variation in the ESR (12). The duration (in minutes) of muscle stiffness (MS) was recorded. The pain scale (S) was represented by a 10-cm horizontal visual analog scale (13). The ESR was measured by the Westergren method (14). Hemoglobin, alkaline phosphatase, and y-glutamyl transferase were estimated by standard laboratory methods, and CR was measured by electroimmunoassay as previously described (15). The coefficient of variation of CR values was <lo% both between and within assays, and the lower limit of sensitivity of the test was 0.1 mgldl. For healthy subjects, the serum CR concentration is <0.3 mgidl in 90% of the subjects and < 1.O mg/dl in 99% (16). The statistical significance of correlations between the ESR values and MS or S was calculated using linear regression analysis, and the significance of correlations between CR levels and MS or S was determined using Spearman s rank correlation coefficient. Student s t-test was used to analyze the significance of differences in hemoglobin concentration obtained over time. RESULTS At presentation to the clinic, and before initiation of steroid therapy, both the CR concentration and the ESR were elevated in all patients. rednisolone caused a rapid improvement in symptoms, which was closely paralleled by a fall in the CR value in all patients (Figure l), so that the CR level was normal in 11 of 13 patients by day 7, and in 12 of 13 patients by 15 Serum CR (mg /dl t I I I I Days Figure 1. Effect of steroid therapy on serum C-reactive protein (CR) concentration in 13 patients with polymyalgia rheumatica.

3 CR IN MR 385 M= (min) 2oo CR (mg/dl) 0 Ti I 1 I Days Figure 2. Response to steroid therapy of subjective and objective indices of disease activity in polymyalgia rheumatica. For muscle stiffness (MS), the pain scale (S), and the erythrocyte sedimentation rate (ESR), each point represents the mean 2 SD; for C- reactive protein (CR), each point represents the median and interquartile range. Table 1. Correlation between subjective and objective indices of disease activity during steroid treatment of polymyalgia rheumatics* CR with MS r, ESR with MS r CR with S r\ ESR with S r C < < ( < < < c < ~ ~~~~~~ ~ ~ * CR = C-reactive protein; MS = muscle stiffness; ra = Spearman s correlation coefficient; ESR = erythrocyte sedimentation rate; r = linear correlation coefficient; = not significant; S = pain scale. See atients and Methods for details. day 14. In marked contrast, the ESR responded much more slowly (Figure 2). The different response rates of these 2 nonspecific indices of disease activity were reflected by significantly higher correlation coefficients between the CR level and the subjective clinical variables than those between the ESIf. and these variables (Table 1). The serum concentrations of hepatic enzymes, alkaline phosphatase, and y-glutamyl transferase, were elevated in a proportion of patients, presumably reflecting the systemic nature of the disease in these individuals. All patients with a high y-glutamyl transferase concentration (7 of 13) also had elevated levels of alkaline phosphatase. Two other patients presented with high levels of alkaline phosphatase, but without abnormal y-glutamyl transferase levels. The levels of these enzymes fell during induction of remission but did so more slowly than the CR or even the ESR, and they did not correlate closely with the clinical manifestations (data not shown). Since there were only 2 patients with temporal arteritis in this series, it was not possible to conduct any statistical analysis; however, there seemed to be no difference in the quality of these patients symptomatic or objective responses to prednisolone. Similarly, there was no difference in response between patients with raised levels of hepatic enzymes and those without. A further, interesting, feature of MR observed in this study was that, although there was, overall, no significant anemia at presentation (hemoglobin gmidl, mean k SD), the hemoglobin concentration rose steadily over the first 14 days of treatment ( gm/dl on day 3, gm/dl on day 7, and 13.31? 0.93 gm/dl on day 14). The value obtained on day 14 was significantly higher than that obtained at presentation ( < 0.005). DISCUSSION The CR is the classic acute-phase plasma protein which is produced by hepatocytes in response to most forms of tissue injury, inflammation, or infection (17). Its concentration in serum increases rapidly, from trace amounts in healthy subjects to levels which closely reflect the extent and activity of underlying disease. With spontaneous or therapeutically induced remission, the serum CR value falls equally as quickly, with a half-life of 5-8 hours. Measurement of serum CR has been well established as a sensitive means of objectively assessing disease activity (18).

4 386 MALLYA ET AL In contrast, the ESR depends on the plasma concentration of fibrinogen, immunoglobulin, and some acute-phase globulins, all of which have halflives of days or weeks, as well as on the number, size, and conformation of the erythrocytes (19). Therefore, the ESR generally responds more slowly to exacerbation and to remission of disease activity than does CR. Measurements of CR, other acute-phase proteins, and of ESR in patients with MR have been reported previously (7,8). However, in one report (7), although many patients were studied, many of them were tested more than once, the number of tests per patient varied, and yet all the results were pooled together for analysis. Furthermore, only some of the individuals were studied serially during progress of their disease. In the other study ( 9, only semiquantitative and relatively insensitive assays for CR were used. For these reasons, information may have been obscured; nonetheless, a clear correlation of CR and ESR with each other and with disease activity was observed. Although we investigated a smaller number of patients, our study was prospective, each individual was very carefully assessed clinically with respect to the major symptoms of muscle stiffness and pain, and ESR and CR levels were measured over the period when clinical changes were occurring most rapidly in response to introduction of steroid therapy. Our results show clearly that a fall in CR value occurred rapidly, closely paralleling the improvement in symptoms, and did so more quickly and over a greater incremental range than did the ESR. The serum CR concentration was restored to normal by steroid therapy at the same time the symptoms were abolished. In contrast, although the ESR fell, it remained above normal in many patients. It is interesting to compare these results with those obtained from monitoring the behavior of serum CR in other inflammatory diseases of unknown etiology, particularly as it relates to treatment with steroids and other antiinflammatory or immunosuppressive drugs. For example, in systemic vasculitis (including polyarteritis nodosa, microscopic polyarteritis, and Wegener s granulomatosis), treatment with both cyclophosphamide and steroids seems to be required to induce remission and control the disease. However, when this is achieved, the CR level falls rapidly to normal and remains there as long as remission is maintained (20,21). Also during this phase, there is no extension of lesions or deterioration of organ function. In rheumatoid arthritis, however, in which the serum CR concentration closely reflects clinical and radiologic assessment of disease activity, it is rare for the CR value to fall within the normal range-even during clinical remission and even while receiving steroid treatment (22,23). This may be because the dosage required to completely abolish disease activity is so high that an unacceptable incidence of side effects occurs, and such steroid dosages are therefore rarely given. The therapeutic response to steroids in MR patients is known to be rapid and dramatic, so much so that initiation of steroid therapy is sometimes used as a diagnostic test (1 1). Nevertheless, an objective test for disease activity remains important for proper management of the MR patient, and not simply as a means of independently confirming the diagnostic impression of clinical improvement. Individuals differ in their subjective response to and reporting of symptoms such as muscle pain and stiffness, and the patient s assessment of these conditions may be complicated by the euphoric effect of steroids. Our results demonstrate that the behavior of serum CR, unlike that of the ESR, reflects precisely and concurrently the classic response to steroid treatment. Furthermore, for all patients whose CR decreased to within the range of normal, their disease remained in remission, with minimal steroid dosage, for the next 12 months. REFERENCES 1. Barber HS: Myalgic syndrome with constitutional effects: polymyalgia rheumatica. Ann Rheum Dis 16: , Calamia KT, Hunder GG: Clinical manifestations of giant cell (temporal) arteritis. Clin Rheum Dis 6: , Hunder GG, Allen GL: The relationship between polymyalgia rheumatica and temporal arteritis. Geriatrics 28~ , Malmvall BE, Bengtsson BA: Giant cell arteritis: clinical features and involvement of different organs. Scand J Rheumatol 7: , Healey LA, Wilske KR: Manifestations of giant cell arteritis. Med Clin North Am 61: , Ellis ME, Ralston S: The ESR in the diagnosis and management of the polymyalgia rheurnaticdgiant cell arteritis syndrome. Ann Rheum Dis 42: , ark JR, Jones JG, Hazleman BL: Relationship of the erythrocyte sedimentation rate to acute phase proteins in polymyalgia rheumatica and giant cell arteritis. Ann Rheum Dis 40: , 1981

5 CR IN MR Eshaghian J, Goeken JA: C-reactive protein in giant cell (cranial, temporal) arteritis. Ophthalmology 87: , Dickson ER, Maldonado JE, Sheps SG, Cain JA: Systemic giant-cell arteritis with polymyalgia rheumatica: reversible abnormalities of liver function. JAMA 224: , Huston KA, Hunder GG, Lie JT, Kennedy RH, Elveback LR: Temporal arteritis: a 25-year epidemiologic, clinical and pathologic study. Ann Intern Med 88: , Hunder GG, Hazleman BL: Giant cell arteritis and polymyalgia rheumatica, Textbook of Rheumatology. Vol. 2. Edited by WN Kelley, ED Harris Jr, S Ruddy, CB Sledge. hiladelphia, WB Saunders, 1981, pp I I Mallya RK, Berry H, Mace BEW, de Beer FC, epys MB: Diurnal variation of erythrocyte sedimentation rate related to feeding. Lancet i: , Berry H, Huskisson EC: Treatment of rheumatoid arthritis. Clin Trials J 9:13-15, International Committee for Standardisation in Haematology : Reference method for the erythrocyte sedimentation rate (ESR) test on human blood. Br J Haematol 23: , Fagan EA, Dyck RF. Maton N, Hodgson HJF, Chadwick VS, etrie A, epys MB: Serum levels of C- reactive protein in Crohn s disease and ulcerative colitis. Eur J Clin Invest 12: , Shine B, de Beer FC, epys MB: Solid phase radioim- munoassays for C-reactive protein. Clin Chim Acta 117:13-23, epys MB: C-reactive protein fifty years on. Lancet i: , epys MB, Baltz ML: Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid A protein. Adv Immunol 34: , epys MB: Acute phase phenomena, The Science and ractice of Clinical Medicine: Rheumatology and Immunology. Edited by AS Cohen. New York, Grune & Stratton, 1979, pp Hind CRK, Winearls CG, Lockwood CM, Rees AJ, epys MB: Objective monitoring of activity in Wegener s granulomatosis by measurement of serum C- reactive protein concentration. Clin Nephrol 2 I : , Hind CRK, Savage CO, Winearls CG, epys MB: Objective monitoring of disease activity in polyarteritis by measurement of serum C-reactive protein concentration. Br Med J 288: , Amos RS, Constable TJ, Crockson RA, Crockson A, McConkey B: Rheumatoid arthritis: relation of serum C- reactive protein and erythrocyte sedimentation rates to radiographic changes. Br Med J 1: , Mallya RK, de Beer FC, Berry H, Hamilton EDB, Mace DEW, epys MB: Correlation of clinical parameters of disease activity in rheumatoid arthritis with serum concentration of C-reactive protein and erythrocyte sedimentation rate. J Rheumatol 9: , 1982