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- PATIENTS AND METHODS
The course of polymyalgia rheumatica (PMR) is heterogeneous with a variable corticosteroid requirement. A treatment course of 1–2 years is often necessary (1). However, ∼30–50% of the patients have a more chronic, relapsing course and may require low doses of corticosteroids for much longer (2–6). Corticosteroid-related adverse events are common and they are strictly related to cumulative dose. A long-term followup study demonstrated that 65% of patients with PMR had at least 1 serious corticosteroid-related event, such as osteoporotic fractures or diabetes mellitus (7).
To identify the subset of patients who require long-term corticosteroid treatment is essential to guiding treatment strategies. The association from the very beginning of therapy of steroid-sparing agents, such as methotrexate (8), could reduce the serious corticosteroid-related events observed in PMR patients.
Unfortunately, there are no reliable predictors of duration of corticosteroid therapy in PMR. Studies on pretreatment erythrocyte sedimentation rate (ESR) as a prognostic indicator of corticosteroid therapy duration have yielded conflicting results (6, 9–11). Although C-reactive protein (CRP) and interleukin-6 (IL-6) appear to be more sensitive indicators of disease activity, it remains unclear whether they provide any prognostic advantage in clinical practice over ESR (11–16).
The aim of this study was to evaluate and compare the usefulness of ESR, CRP, and IL-6 levels as predictors of relapse or recurrence using detailed followup information from a prospectively studied large cohort of patients with pure PMR.
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- PATIENTS AND METHODS
The clinical and demographic characteristics of the patients are shown in Table 1. Table 2 compares PMR patients with 1 or 2 relapses with those without. The duration of prednisone therapy was significantly longer in patients with relapse/recurrence compared with those without.
Table 1. Demographic and clinical findings of the 94 polymyalgia rheumatica patients*
|Age at onset of disease, years||74 (53–86)|
|Duration of symptoms before diagnosis, months||3 (1–29)|
|Duration of therapy, months||18 (6–96)|
|Duration of followup, months||35 (12–96)|
|Systemic symptoms or signs (fever, anorexia, weight loss) %||53|
|Morning stiffness at diagnosis, hours||3 (1–6)|
|Peripheral arthritis, %||14.9|
|Patients with ≥1 relapse/recurrence, no. (%)||47 (50.0)|
|Patients with ≥2 relapse/recurrence, no. (%)||24 (25.5)|
|Starting prednisone dosage, mg/day||17.5 (10.0–25.0)|
Table 2. Comparison between the demographic and clinical findings of the polymyalgia rheumatica patients with and without relapse/recurrences*
| ||Patients without relapse/recurrence (n = 47) Group A||Patients with ≥1 relapse/recurrence (n = 47) Group B||Patients with ≥2 relapse/recurrences (n = 24) Group C||A versus B P||A versus C P|
|Age at onset of disease, years||75 (58–86)||74 (53–82)||75 (65–82)||NS||NS|
|Duration of symptoms before diagnosis, months||2 (1–10)||4 (1–29)||4 (1–29)||0.001||0.0001|
|Duration of therapy, months||13 (6–96)||26 (6–89)||29 (6–89)||0.0001||0.0001|
|Duration of followup, months||28 (12–83)||38 (21–96)||38 (28–96)||0.004||0.002|
|Systemic symptoms or signs (fever, anorexia, weight loss) no./n (%)||20/47 (42.6)||24/47 (51.1)||14/24 (58.3)||NS||NS|
|Morning stiffness at diagnosis, hours||3 (1–6)||3 (1–5)||3 (2–4)||NS||NS|
|Peripheral arthritis, no./n (%)||8/47 (17.0)||6/47 (12.8)||4/24 (16.7)||NS||NS|
|Starting prednisone dosage, mg/day||12.5 (10.0–25.0)||20.0 (10.0–25.0)||25.0 (10.0–25.0)||NS||NS|
Table 3 shows acute phase protein values at diagnosis and at different times during the followup period. A significant reduction in ESR, CRP, and IL-6 values was observed after the first month of therapy and persisted for the entire 24-month followup. Table 4 shows the number and the percentages of patients with elevated acute-phase reactants at different times during the followup period. ESR, CRP, and IL-6 at baseline were elevated in 91.5%, 98.9%, and 92.6% of PMR patients, respectively. After 1 month of therapy, the percentages fell to 13.2%, 41.9%, and 37.2%, respectively. About one-third of the patients had elevated levels of CRP and IL-6 at the different scheduled times during the first year of followup.
Table 3. Acute phase protein values at diagnosis and at different times during the followup*
| ||Baseline||1st month||3rd month||6th month||12th month||24th month|
|ESR mm/hour||68 (14–128)||14 (2–97)†||13 (2–51)†||15 (1–61)†||14 (1–76)†||15 (1–72)†|
|CRP mg/dl||3.5 (0.7–18.2)||0.5 (0.2–5.4)†||0.4 (0.2–4.2)†||0.4 (0.2–5.6)†||0.4 (0.2–8.7)†||0.4 (0.2–8.2)†|
|IL-6 pg/ml||22.5 (0.5–159.6)||2.8 (0.1–101.3)†||2.1 (0.1–104.2)†||2.2 (0.1–94.3)†||2.0 (0.1–96.9)†||1.7 (0.1–82.2)†|
Table 4. Patients with elevated level of acute phase proteins at different times during the followup*
| ||Baseline||1st month||3rd month||6th month||12th month||24th month|
|ESR||86/94 (91.5)||12/91 (13.2)†||10/88 (11.4)†||17/93 (18.3)†||21/92 (22.8)†||15/82 (18.3)†|
|CRP||92/93 (98.9)||39/93 (41.9)†||34/93 (36.5)†||37/93 (39.8)†||36/92 (39.1)†||20/82 (24.4)†|
|IL-6||87/94 (92.6)||35/94 (37.2)†||24/94 (25.5)†||30/94 (31.9)†||25/91 (27.5)†||11/78 (14.1)†|
Table 5 shows a subset of patients who presented persistently elevated values of CRP and IL-6 during the followup at the 4 time intervals considered (0–3, 0–6, 0–12, and 0–24 months). No patient had persistent elevation of ESR.
Table 5. Patients with persistently elevated ESR, CRP, and IL-6 levels at different time intervals during the followup*
| ||0–3 months||0–6 months||0–12 months||0–24 months|
|CRP||24/93 (25.8)||14/93 (15.1)||8/92 (8.7)||6/81 (7.4)|
|IL-6||18/94 (19.1)||12/94 (12.8)||9/91 (9.9)||5/78 (5.1)|
Cox proportional hazards modeling identified the variables related to the acute phase reactants that independently increased the risk of at least 1 or 2 relapses or recurrences (Table 6). Elevated ESRs at diagnosis were correlated to an increased risk of developing ≥1 relapse or recurrence, whereas elevated levels of CRP and IL-6 at diagnosis were not. Given the low number of cases, it was not possible to compute the relative risk of having ≥2 relapses or recurrences for elevated levels of ESR and CRP at diagnosis. We compared the frequencies of relapses or recurrences between quartiles of ESR, CRP, and IL-6 values at diagnosis. However, the frequencies of relapses or recurrences did not differ according to the level of the inflammatory marker.
Table 6. Relative risk of having ≥1 or ≥2 relapses/recurrences among patients with polymyalgia rheumatica for acute phase reactants*
|Variable||At least 1 relapse/recurrence||At least 2 relapses/recurrences|
|Relative risk*||95% CI||P||Relative risk*||95% CI||P|
|ESR 1st month||0.6||0.2–1.7||NS||0.4||0.05–3.2||NS|
|ESR 3rd month||3.3||1.3–8.4||0.01||4.0||1.2–13.7||0.03|
|ESR 6th month||5.3||2.5–11.2||0.0001||4.7||1.7–13.0||0.003|
|ESR 12th month||2.1||1.1–4.1||0.03||3.7||1.5–9.5||0.006|
|ESR 24th month||1.3||0.5–3.3||NS||5.4||1.5–19.7||0.01|
|CRP 1st month||0.9||0.5–1.8||NS||1.0||0.4–2.6||NS|
|CRP 3rd month||1.3||0.7–2.8||NS||1.0||0.4–2.6||NS|
|CRP 6th month||3.1||1.7–5.8||0.0001||1.4||0.6–3.3||NS|
|CRP 12th month||2.6||1.4–4.9||0.003||5.1||1.9–13.5||0.001|
|CRP 24th month||2.5||1.2–5.0||0.01||2.5||1.0–6.1||0.05|
|CRP 0–3 months||1.4||0.7–2.9||NS||1.1||0.4–3.1||NS|
|CRP 0–6 months||3.7||1.5–9.2||0.005||2.1||0.6–7.6||NS|
|CRP 0–12 months||4.7||1.7–12.6||0.002||3.4||0.8–15.5||NS|
|CRP 0–24 months||4.0||1.3–12.2||0.02||5.4||1.1–26.2||0.04|
|IL-6 1st month||2.0||1.0–3.7||0.04||2.3||1.0–5.5||0.06|
|IL-6 3rd month||1.1||0.5–2.5||NS||1.4||0.5–4.1||NS|
|IL-6 6th month||1.6||0.8–3.1||NS||4.3||1.7–11.0||0.003|
|IL-6 12th month||2.9||1.5–5.5||0.001||3.8||1.5–9.4||0.004|
|IL-6 24th month||1.6||0.7–3.7||NS||3.1||1.2–8.1||0.02|
|IL-6 0–3 months||2.0||0.9–4.6||NS||3.6||1.3–9.9||0.01|
|IL-6 0–6 months||1.5||0.6–3.9||NS||4.5||1.4–14.3||0.01|
|IL-6 0–12 months||1.8||0.6–5.0||NS||12.8||3.4–48.3||0.0001|
|IL-6 0–24 months||1.4||0.4–5.1||NS||7.0||1.6–31.7||0.01|
Elevated levels of ESR at the 3rd, 6th, and 12th months were significantly associated with an increased risk of developing at least 1 or 2 relapses/recurrences, as were elevated levels of CRP at the 12th and 24th months. Elevated levels of IL-6 at the 12th month were significantly associated with an increased risk of developing at least 1 or 2 relapses or recurrences, whereas elevated levels at the 6th and 24th months were associated with an increased risk of developing at least 2 relapses/recurrences.
Persistently elevated levels of CRP and IL-6 were significantly associated with an increased risk of developing relapses or recurrences. Patients with persistently elevated levels of CRP during the first, 6th, 12th, and 24th months of followup had a risk of developing ≥1 relapse/recurrence that was 2–5 times higher than that of the patients without. Patients with persistently elevated levels of IL-6 had a risk of developing ≥2 relapses/recurrences that was 4–13 times higher than that of the patients without.
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- PATIENTS AND METHODS
The aim of our prospective study was to determine whether acute phase reactants could be used to differentiate patients with different disease severity to be able to predict therapy duration. It has been suggested that there are 2 subsets of PMR patients, one of which presents mild self-limiting disease requiring 1–2 years of treatment, and the other is made up of patients with a more chronic, relapsing course of disease who may require low doses of corticosteroids for several years (1–6).
Of all patients with PMR, 65% have at least 1 serious corticosteroid-related event; in particular, the risk of vertebral fractures is 5 times greater among women with PMR (7). A cumulative dose of prednisone of at least 2 gm is one of the variables that independently increased the risk of adverse events. Therefore, efforts should be made to maintain the corticosteroid dosages at the lowest levels possible for the shortest periods of time, particularly in patients with diabetes, osteoporotic fractures, hypertension, glaucoma, and other conditions negatively affected by higher corticosteroid doses.
Recently, a double blind, placebo-controlled study showed a steroid-sparing effect of methotrexate associated to corticosteroids (21). Furthermore, a pilot study showed that infliximab may have a steroid-sparing effect in the treatment of PMR patients who are resistant to corticosteroid therapy and have had corticosteroid-related side effects (22). Therefore, some evidence is accumulating that certain medications could be useful as steroid-sparing agents in PMR, reducing the corticosteroid exposure and thus the adverse effects related to corticosteroids.
The identification of reliable serologic predictors of the duration of corticosteroid therapy will make it possible to define the patients with a relapsing course who require long-term therapy and could benefit from the beginning from the association with steroid-sparing drugs. Few studies have evaluated the predictor role of acute phase markers. Conflicting results have been reported on the usefulness of pretreatment ESR as a prognostic indicator for duration of therapy (6, 9–11). CRP and IL-6 seem to be more sensitive indicators of disease activity (12, 23–25). In particular, IL-6 appears to be a potentially useful biologic marker of disease activity in PMR. IL-6 is the chief stimulator of the production of most acute-phase proteins. Increased production of IL-6 is a characteristic finding in patients with PMR, and corticosteroids rapidly reduce the levels of circulating IL-6 (11, 15, 16, 25). However, it is unclear if CRP and IL-6 have some advantages in clinical practice over ESR (11–16).
Our study confirmed that CRP was more sensitive than ESR for PMR diagnosis. CRP was elevated in 98.9% of the patients at diagnosis, whereas ESR was elevated in 91.5%. Standardized diagnostic and classification criteria are needed for PMR, and CRP levels could be included as diagnostic criteria.
We found that pretreatment ESR was of some prognostic value, whereas pretreatment CRP and IL-6 levels were not. Patients with elevated ESRs at diagnosis had a higher risk of having ≥1 relapse or recurrence. However, the low number of patients with normal ESR values at diagnosis limited the statistical power of this analysis.
Similar to previous studies (16, 25, 26), we observed the presence of a high percentage (around one-third during the first year) of patients with elevated levels of CRP or IL-6 at different times during the followup despite clinical remission. However, the most interesting finding was the evidence of a subgroup of patients who presented persistently elevated values of CRP and IL-6 during the followup period. The final multivariate models revealed that persistently elevated levels of CRP and IL-6 were significantly associated with a higher risk of developing relapses or recurrences.
Our current data support previous observations. Schreiber and Buyse found that patients whose CRP levels persisted to be elevated after 7 days of therapy had a longer treatment course and required higher amounts of corticosteroids (24). Weyand et al showed that persistently elevated levels of IL-6 after 1 month of treatment characterized PMR patients who required higher initial corticosteroid dosages and had to take them for longer (11).
No patient presented persistently elevated ESR values, confirming that this laboratory parameter is less sensitive than CRP and IL-6 in measuring persistent acute phase responses and in identifying patients at higher risk of developing relapses or recurrences. A possible conclusion from the present study is that the corticosteroid dosage should be increased to completely suppress CRP or IL-6, or a steroid-sparing agent should be added to therapy for patients with persistent elevation of CRP or IL-6 levels after 6 months of therapy. The higher risk of disease relapse suggests that these patients are undertreated and that the insufficient suppression of inflammation affects the long-term outcome of these patients.
Potential advantages and limitations of our study warrant discussion. We treated all patients with a fixed schedule of prednisone dose tapering, defined relapses and recurrences in a strict way, and determined all the 3 main acute phase reactants at different fixed times during a long-term followup of at least 2 years. Furthermore, we included an adequate number of patients (n = 94) with pure PMR, eliminating the possible confounding effect of patients with giant cell arteritis. However, the modest sample size of patients with ≥2 relapses or recurrences somewhat limited the statistical power of this analysis.
In conclusion, our study shows that despite its apparent control of clinical symptoms, corticosteroids do not adequately control the inflammatory process in a subset of patients with PMR identifiable by the persistent elevation of CRP and IL-6 levels after initiation of prednisone therapy. Recognizing this subset of patients with chronic, relapsing disease who require long-term corticosteroid treatment is essential to guiding treatment strategies.