1. No category

Joint Bone Spine 73 (2006) 599–605
http://france.elsevier.com/direct/BONSOI/
Clinical-state-of-the-art
Polymyalgia rheumatica: diagnosis and treatment
Martin Soubrier*, Jean-Jacques Dubost, Jen-Michel Ristori
Service de Rhumatologie, CHU de Clermont-Ferrand, place Henri-Dunant, BP 69, 63003 Clermont-Ferrand cedex 1, France
Received 1 August 2006; accepted 6 September 2006
Available online 12 October 2006
Abstract
Polymyalgia rheumatica (PMR) typically manifests as inflammatory pain in the shoulder and/or pelvic girdles in a patient over 50 years of
age. This condition was long underrecognized and therefore underdiagnosed. Today, however, overdiagnosis may occur. Physicians must be
aware that many conditions may simulate PMR, including diseases that carry a grim prognosis or require urgent treatment. PMR may be the
first manifestation of giant cell arteritis, and a painstaking search for other signs is mandatory. PMR may inaugurate other rheumatologic diseases
such as rheumatoid arthritis, RS3PE syndrome, spondyloarthropathy, systemic lupus erythematosus (SLE), myopathy, vasculitis, and chondrocalcinosis. Finally, PMR may be the first manifestation of an endocrine disorder, a malignancy, or an infection. Failure to respond to glucocorticoid therapy should suggest giant cell arteritis, malignant disease, or infection. Ultrasonography may assist in the diagnosis by showing bilateral
subdeltoid bursitis. Glucocorticoids are the mainstay of the treatment of PMR. Although the optimal starting dosage and tapering schedule are not
agreed on, a low starting dosage and slow tapering may decrease the relapse rate. Methotrexate is probably useful when glucocorticoid dependency develops. In contrast, TNF-α antagonists are probably ineffective.
© 2006 Elsevier Masson SAS. All rights reserved.
Keywords: PMR; Giant cell arteritis; RS3PE; Rheumatoid arthritis; Methotrexate
1. Introduction
Polymyalgia rheumatica (PMR) is characterized by inflammatory pain and stiffness of the shoulder and/or pelvic girdles
accompanied with laboratory evidence of severe inflammation
in a patient older than 50 years of age [1–4]. Although this
independent entity carries a good prognosis, it can occur as a
manifestation of a number of diseases, some of which are serious or require immediate treatment [1–4]. The distinction is
often impossible to achieve given the absence of pathognomonic signs, and nosological confusion probably contributes substantially to the differences in reported manifestations and
treatments of PMR.
2. Epidemiology
The lack of universally accepted classification criteria for
PMR complicates the interpretation of epidemiological data.
* Corresponding
author.
E-mail address: [email protected] (M. Soubrier).
1297-319X/$ - see front matter © 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.jbspin.2006.09.005
The disease is exceedingly rare before 50 years of age. Its prevalence after 50 years of age has been estimated at 1 case per
133 population [5]. The incidence increases with age [3,6].
PMR is more common in women than in men in all affected
age groups, although the difference may be smaller in older
populations [6]. A North-to-South gradient has been reported.
In Norway, the annual rate after 50 years of age was
11.2/10,000 between 1987 and 1994 [7]. Annual rates of
8.4/10,000 in the UK and 1.9/10,000 in Spain have been
reported [6,8]. These geographic variations may be ascribable
to genetic factors. Supporting this hypothesis is the high incidence of PMR in Minnesota, where a large proportion of the
population is of North European descent [9]. Until recently, the
incidence of PMR was thought to be stable [9]. However, a
recent study from the UK showed an increase in the incidence
of the disease from 6.9/10,000 patient-years in 1990 to
9.3/10,000 patient-years in 2001 [6].
3. Etiology
Seasonal variations in the incidence of PMR have been
reported, suggesting a role for an infectious agent [6,10–13].
600
M. Soubrier et al. / Joint Bone Spine 73 (2006) 599–605
Several organisms have been incriminated, including adenovirus, respiratory syncytial virus, type 1 parainfluenza virus,
parvovirus B19, Mycoplasma pneumoniae, and Chlamydia
pneumoniae [10–13]. Other studies found no evidence of seasonal variations or associations with infectious agents [14,15].
The ethnic distribution and reports of familial cases suggest a
role for genetic factors. The HLA DRB1*04 and DRB1*01
alleles are associated with PMR and perhaps also with greater
severity of the disease [16,17]. Genetic polymorphisms for
intercellular adhesion molecules (ICAM-1), TNF-α, and the
IL-1 receptor antagonist may influence the susceptibility to
PMR [3]. Inappropriate secretion of serum cortisol, ACTH,
and dehydroepiandrosterone sulfate has been documented, suggesting a pathogenic role for adrenal gland dysfunction [18–
20].
4. Clinical manifestations
Inflammatory pain with morning stiffness for longer than
1 hour in the shoulder girdle (70–95% of patients) and/or pelvic girdle (50–70%) is the typical presentation. Pain for at least
1 month is required for the diagnosis. The cervical or lumbar
spine may be affected also. The pain may be confined to one
side at first but rapidly becomes bilateral. One-third of patients
have constitutional symptoms such as low-grade fever, asthenia, anorexia, and weight loss. The marked functional impairment contrasts with the paucity of the physical findings. Examination of the shoulders fails to disclose objective evidence of
inflammation. The active range of motion of the shoulders may
be diminished, most notably in the morning. Passive range of
motion is occasionally reduced. Muscle strength is normal.
Peripheral manifestations seem common [21]. Thus, 79
(45%) of 177 patients followed up prospectively in Italy exhibited peripheral manifestations [21]. Asymmetric polyarthritis
without joint erosions was noted in 45 patients (25%), carpal
tunnel syndrome in 24 (14%), and swelling of the hands in
(12%). These peripheral manifestations coincided with girdle
involvement in 69% of cases and occurred during follow-up
in the absence of girdle symptoms in 30% of cases, indicating
a relapse. Peripheral arthritis may develop, most notably in
women with a history of multiple relapses over several years
of treatment. Peripheral edema predominantly affects older
patients treated with low-dose glucocorticoid therapy for a
short period.
5. Laboratory tests
Erythrocyte sedimentation rate (ESR) elevation to more than
40 mm/h is a major diagnostic criterion for PMR. However, the
value is normal in 7–20% of patients [22–25]. C-reactive protein (CRP) elevation with a normal ESR has been reported
[22]. IL-6 elevation is common [26,27], and presence of this
abnormality despite treatment indicates an increased risk of
relapse [26,27]. However, the IL-6 assay is not widely available. Cholestasis without jaundice is found in 20–30% of cases
[3]. Tests are negative for rheumatoid factors and antinuclear
antibodies. Muscle enzyme levels are normal.
6. Imaging studies
Studies using ultrasonography and magnetic imaging resonance (MRI) have established that bursitis and synovitis are
very common in patients with PMR [28,29]. Acromiodeltoid
bursitis and subdeltoid bursitis were present in 55 of 57
patients in one study [29], compared to only 25 of 114 controls
(46 with rheumatoid arthritis, 21 with spondyloarthropathies,
six with connective tissue diseases, 35 with osteoarthritis, and
six with fibromyalgia). Bursitis was present in 12 of the 46
patients with rheumatoid arthritis and 7 of the 21 patients
with spondyloarthropathies. Of the 55 patients with bursitis
and PMR, 53 had bilateral bursitis, compared to only 1 of the
25 controls with bursitis. Bilateral bursitis had 92.9% sensitivity, 99.1% specificity, and 98.1% positive predictive value for
PMR [29]. In another study [30], however, bilateral bursitis
was noted in only 35 (70%) of 50 patients with PMR, compared to 22 (44%) of 50 patients with rheumatoid arthritis.
MRI studies have shown tenosynovitis in patients with peripheral edema [31].
7. Diagnostic criteria
Diagnostic criteria for the diagnosis of PMR are empirical.
The first criteria were developed by Bird et al. in 1979
(Table 1) [32]. However, they fail to include pelvic girdle
involvement, a prompt response to glucocorticoid therapy, or
exclusion of other diagnoses. Among the many other criteria
sets [33], those developed by Hunder and Healey are widely
used in the US and UK (Table 1) [34,35]. The only difference
between them is that a prompt response to glucocorticoid therapy is included in the Healey set [3]. Not surprisingly, sensitivity is highest for the Bird criteria set (99.5%), followed by
the Hunder set [33].
Table 1
A: Criteria for PMR developed by Bird and colleagues: three of the following
seven features are required; B: criteria for PMR developed by Healey and
colleagues: all six criteria are required
A
1°
2°
3°
4°
5°
6°
7°
Bilateral shoulder pain and/or stiffness
Bilateral upper arm tenderness
Onset of illness within 2 weeks
ESR >40 mm/h
Morning stiffness >1 hour
Age >65 years
Depression or weight loss or both
B
1° Pain for at least 1 month at two or more of the following sites: shoulders,
pelvic girdle, and cervical spine
2° Morning stiffness >1 hour
3° Age >50 years
4° ESR >40 mm/h
5° Exclusion of other diagnoses
6° Prompt and marked response to glucocorticoid therapy in a dosage
<20 mg/day
M. Soubrier et al. / Joint Bone Spine 73 (2006) 599–605
601
8. Differential diagnosis
8.2. Rheumatoid arthritis
Inflammation of the girdles is a common but misleading
inaugural manifestation in many conditions that are far more
severe than PMR. In a recent study of 208 patients who had
manifestations consistent with PMR, 23 patients were found to
have another disease [36]. Among these other diagnoses, 10
were malignancies (five solid cancers and five hematological
malignancies) and 10 were rheumatologic diseases (seronegative polyarthritis in five cases, lupus in two cases, polymyositis
in one case, and ankylosing spondylitis in one case). The
remaining three patients had infective endocarditis, hypothyroidism, and Parkinson disease, respectively.
Symptom onset after 60 years of age is usually taken to
define late-onset rheumatoid arthritis. The sex distribution
was balanced in some studies and biased toward females in
others [43–45]. The onset is often abrupt, with arthritis developing within 24 hours in 40% of cases. Symmetric joint involvement is noted in 70% of cases. The small and medium-sized
joints are affected in 90% of cases and the large joints (most
notably the shoulders) in 40%. The symptoms are often interpreted as indicating PMR in this age group. Anti-CCP assays
may help to establish the diagnosis of rheumatoid arthritis with
initial involvement of the proximal limb joints [46,47]. In one
study [46], anti-CCP assays were negative in 49 patients with
PMR but were positive in 35 of 57 patients with late-onset
rheumatoid arthritis; in this last subgroup, of the 10 patients
who had proximal limb joint involvement, two tested positive
for anti-CCP antibodies. Of 41 patients in this study who had
typical rheumatoid arthritis, 38 (92.7%) had anti-CCP antibodies. Finally, none of the 24 healthy controls tested positive for
anti-CCP antibodies. Anti-CCP was 61.4% sensitive and 100%
specific for the diagnosis of late-onset rheumatoid arthritis
[46]. In another study, 1 of 13 patients with PMR tested positive for anti-CCP, in low titers, compared to 9 of 16 patients
with late-onset rheumatoid arthritis; sensitivity was 56% and
specificity 92% for rheumatoid arthritis [47]. In many cases,
only time can distinguish between PMR and late-onset rheumatoid arthritis. In a prospective follow-up study [48] of 349
patients with suspected late-onset rheumatoid arthritis
(N=141), PMR (N=171), or giant cell arteritis (N=37) [48],
nine initial diagnoses of PMR were corrected to rheumatoid
arthritis, and the opposite occurred in five patients. In 29
patients with giant cell arteritis, proximal limb manifestations
inaugurated the disease. Overall, the first diagnosis was wrong
in 10% of patients [48].
8.1. Giant cell arteritis
The most common differentials discussed in everyday practice are giant cell arteritis and late-onset rheumatoid arthritis.
The association between PMR and giant cell arteritis is firmly
established. Several arguments suggest that these two conditions may belong to the same disease spectrum. Thus, 50% of
patients with giant cell arteritis have symptoms of PMR, and
15–20% of patients with PMR have temporal arteritis. The two
diseases share the same genetic susceptibility factors [2].
Increased fluorodeoxyglucose uptake by affected arteries has
been reported in patients with giant cell arteritis [37–39].
Blockmans et al. [37,38] were the first to document increased
arterial uptake in PMR, supporting the existence of vascular
lesions in this disease. However, recent work by the same
group seems to contradict the first studies, at least in part.
Thus, proximal limb pain in patients with giant cell arteritis
correlated with increased uptake by the shoulders but not by
the subclavian and axillary arteries [38]. Among the 35 patients
with PMR, only 11 had increased uptake by the subclavian
arteries, and the increase was modest; uptake was high at the
shoulders in 33 patients and at the hips in 31 [39]. In a study of
gallium scintigraphy, uptake by the temporal arteries was
increased in patients with giant cell arteritis [40]. An increase,
albeit of smaller magnitude, was also found in nine patients
meeting Healey’s criteria for PMR, compared to controls
[41]. In practice, when PMR is suspected, a painstaking search
must be undertaken for symptoms and signs of giant cell arteritis, such as headaches, intermittent claudication of the jaw,
hyperesthesia of the scalp, and abnormal temporal artery to
palpation. If giant cell arteritis is suspected, a temporal artery
biopsy should be obtained and appropriate glucocorticoid therapy initiated. A temporal artery biopsy is also in order in
patients who fail to respond to low-dose glucocorticoid therapy
and in those whose tests for inflammation worsen despite treatment [2,3]. The place for Doppler ultrasonography of the temporal artery remains to be determined. Findings suggestive of
giant cell arteritis include vessel wall thickening due to inflammatory edema. However, in 102 patients with apparently pure
PMR, only 8% had a positive halo sign [42].
8.3. RS3PE
The relationship between remitting seronegative symmetrical synovitis with pitting edema (RS3PE) and PMR is controversial [49]. These two conditions share many features, including occurrence in older individuals, an abrupt onset, symmetric
manifestations, a response to low-dose glucocorticoid therapy,
and absence of relapses after 2 years of treatment. Peripheral
manifestations may occur in PMR, and shoulder pain is common in RS3PE. Furthermore, RS3PE may develop before or
after PMR. The numerous similarities suggest that these two
conditions may belong to the same entity, with RS3PE being
a distinctive clinical pattern of PMR characterized by the
development of edema.
8.4. Late-onset peripheral spondyloarthropathy (LOPS)
Patients with LOPS may present with inflammatory neck
and shoulder pain, constitutional symptoms, and marked ESR
elevation. Asymmetric oligoarthritis is suggestive, as well as
602
M. Soubrier et al. / Joint Bone Spine 73 (2006) 599–605
asymmetric pitting edema predominating in the lower limbs.
Even more suggestive is a weaker than expected response to
glucocorticoid therapy. A family history of LOPS and presence
of HLA B27 support the diagnosis. [50].
8.5. Systemic lupus erythematosus (SLE)
SLE may mimic PMR at presentation [51]. Serositis is more
common in elderly patients and suggests SLE [52]. A positive
test for anti-dsDNA confirms the diagnosis. Induced lupus is
common in older individuals and should be painstakingly
looked for, without omitting to ask for a history of betablocker eye drop use [52].
8.6. Vasculitides
The clinical features of micropolyangeiitis may mimic
PMR. Consequently, a urine dipstick test should be done to
look for blood or proteins. A test for antineutrophil cytoplasmic antibody should be obtained at the slightest doubt [4].
8.7. Chondrocalcinosis
Articular chondrocalcinosis may manifest as proximal limb
pain [53]. Patients with chondrocalcinosis are older and more
likely to have arthritis, compared to patients with PMR. In
patients with manifestations that are consistent with PMR, features that suggest chondrocalcinosis include femorotibial
osteoarthritis, ankle arthritis, and tendon calcifications (rotator
cuff and quadricipital tendon) [53]. Ultrasonography of the
shoulders may show bursitis, suggesting PMR, or chondrocalcinosis (calcifications without bursitis) [53]. However, linear
calcifications denoting chondrocalcinosis are common in individuals older than 80 years and may coexist with PMR.
8.8. Polymyositis
Inflammatory muscle disease usually results in weakness of
the shoulder and pelvic girdles, without pain [4]. Routine measurement of muscle enzyme levels rules out this diagnosis.
8.9. Endocrine disorders
Thyroid dysfunction, hyperparathyroidism, and osteomalacia should be ruled out routinely [54].
8.11. Infective endocarditis
Rheumatologic manifestations are common in patients with
infective endocarditis [59] and may mimic PMR [36]. Blood
cultures should be obtained routinely in patients with valve
disease. Infective endocarditis should also be considered in
patients with muscle pain, a fever, and general malaise [59],
as well as in those who fail to respond to glucocorticoid therapy [36].
8.12. Malignant disease and amyloidosis
The presentation in myelodysplasia may simulate PMR
[60], and the manifestations usually respond to glucocorticoid
therapy. Therefore, caution is in order when the initial blood
counts show cytopenia [60]. Multiple myeloma, lymphoma,
and leukemia may also resemble PMR at presentation [36]. A
few cases of amyloidosis with gammopathy presenting as PMR
have been reported [61]. Many malignancies can present as
PMR (e.g. renal carcinoma, gastric adenocarcinoma, colon cancer, pancreatic cancer, prostate cancer, uterine cancer, and
ovarian cancer) [36]. However, a thorough work-up for cancer
should be reserved for patients who fail to respond to glucocorticoid therapy. Patients with PMR are not at increased risk
for hematological malignancies or solid tumors, compared to
controls [62].
PMR is a syndrome, and many differential diagnoses must
be considered. The initial evaluation should rule out the most
common among them (Table 2).
In patients who have no laboratory evidence of inflammation or who fail to respond dramatically to glucocorticoid therapy, clinicians should be prepared to reappraise the diagnosis
(Tables 3 and 4).
Table 2
Suggested investigations for patients with PMR
Full blood cell counts, platelet count
ESR, CRP
Serum protein electrophoresis
Creatinine
Urine dipstick test
Chest radiograph
Anteroposterior radiographs of the
hands and wrists on the same plate
Anteroposterior radiographs of the
forefeet on the same plate
Ultrasonography of the shoulders
Serum calcium and phosphate
ASAT, ALAT, alkaline phosphatase
CPK
Rheumatoid factors, Anti-CCP
ANF
ESR: erythrocyte sedimentation rate; CRP: C-reactive protein level in serum;
ASAT: aspartate aminotransferase; ALAT: alanine aminotransferase; CPK:
creatine phosphokinase; ANF: antinuclear factor.
8.10. Drugs
Table 3
Differential diagnoses in patients with PMR and a normal ESR
Clinical manifestations suggesting PMR have been reported
to occur with statins, conversion enzyme inhibitors, betablockers, and dipyridamole [55–58].
Myositis, myopathy
Endocrine disorders: thyroid gland dysfunction, hyperparathyroidism,
osteomalacia
Drugs: lipid-lowering agents, angiotensin-conversion enzyme inhibitors,
beta-blockers, dipyridamole…
M. Soubrier et al. / Joint Bone Spine 73 (2006) 599–605
Table 4
Differential diagnoses in patients with PMR that fails to respond to
glucocorticoid therapy
Giant cell arteritis
Spondyloarthropathy
Malignancy
Amyloidosis
Infective endocarditis
9. Treatment
Nonsteroidal antiinflammatory drugs have been suggested
to treat mild forms of PMR. In the elderly population targeted
by this disease, however, they carry a high risk of gastrointestinal, renal, and cardiovascular side effects [63].
Glucocorticoid therapy is the mainstay of the treatment of
PMR. The optimal starting dosage is not agreed on and varies
across studies from 15–25 mg/day. A dramatic response with
complete symptom resolution within 48–72 hours can be
expected and supports the diagnosis of PMR. Although lower
dosages (e.g. 10 mg) have been suggested, they induce a less
conclusive response. The starting dosage should be given for
3–6 weeks on average, until the laboratory tests for inflammation return to normal. No studies designed to determine the
optimal tapering schedule are available. In practice, relapses
rarely occur when the dosage is decreased by 10% every 10–
15 days down to 10 mg/day. A slower rate of decrease of about
1 mg every month or 2 months is then used to taper the patient
off the drug. Total treatment duration is usually 2–3 years [3].
Glucocorticoid therapy induces side effects in older patients.
In a prospective cohort study, nearly 65% of patients with
PMR treated with a glucocorticoid alone experienced side
effects [63]. Bone loss prevention requires calcium and vitamin
D supplementation, as well as bisphosphonate therapy. The
main prophylactic measure, however, is use of the lowest possible glucocorticoid dose. A higher starting dose and a faster
tapering rate are associated with a greater risk of relapse [64].
Therefore, a low starting dose and slow tapering are recommended. Isolated ESR elevation does not warrant an increase
in the glucocorticoid dosage. The CRP level is a better parameter for monitoring the course of the disease. The need for a
dosage increase should be considered only if the CRP level
rises or the symptoms recur. The recently developed disease
activity score for PMR (PMR-DAS) [65] is obtained by summing the CRP level (mg/dl), the patient-assessed visual-analogscale score for disease activity, the duration of morning stiffness (min · 0.1), and the ability to lift the arms (3, impossible;
2, below the shoulder; 1, to the shoulder; 3, above the
shoulder). PMR-DAS values lower than 7 indicate inactive disease, between 7 and 17 moderately active disease, and greater
than 17 highly active disease. If studies succeed in determining
a cutoff that defines a relapse, the PMR-DAS may prove useful
for monitoring disease activity under treatment and for avoiding unnecessary exposure to glucocorticoid therapy. Intramuscular methylprednisolone 120 mg every 3 weeks has been evaluated in patients with PMR. Efficacy and safety were good, but
bone loss was not diminished [66]. Methylprednisolone acetate
603
injections into the glenohumeral joints (40 mg four times at 1week intervals) may be a valid alternative to systemic glucocorticoid therapy [67].
Drugs used in an effort to reduce glucocorticoid requirements include hydroxychloroquine, methotrexate, and TNF-α
antagonists. No prospective data on hydroxychloroquine are
available. A 1983 retrospective study of 176 patients showed
that only five patients given a nonsteroidal antiinflammatory
drug combined with an antimalarial drug experienced relapses,
one of which was associated with giant cell arteritis [68].
Double-blind placebo-controlled studies would be of great
interest. Methotrexate as a glucocorticoid-sparing agent was
evaluated in two open-label studies and three placebocontrolled studies, with conflicting results. An open-label
study in 27 patients showed a beneficial effect with a mean
time to remission of 6 months [69]. No benefits were noted
in the other open-label study [70], which was conducted in
108 patients given a diagnosis of PMR between 1989 and
1993. All patients took prednisone 10 mg/day. Patients who
required more than 20 mg/day of prednisone were given methotrexate 7.5 mg/week for 3 months. Adding methotrexate was
associated neither with a glucocorticoid-sparing effect nor with
control of the clinical and laboratory test abnormalities at the
end of the 3-month period. In a placebo-controlled study done
between November 1989 and November 1991, 40 patients with
PMR (including six with giant cell arteritis) were randomized
to prednisone 20 mg/day plus methotrexate 7.5 mg orally per
week or to prednisone 20 mg/day plus a placebo [71]. When
the symptoms abated and the laboratory tests showed resolution of the inflammatory syndrome (ESR <15 mm/h and CRP
<6 mg/l), the prednisone dosage was reduced by 2.5 mg every
3 weeks down to 7.5 mg/day then by 2.5 mg every 6 weeks.
Only 21 patients completed the 2-year follow-up, 11 in the
methotrexate group and 10 in the placebo group. The remission
rate, time to remission, and duration of remission were not significantly different in the two groups. Neither was the cumulative glucocorticoid dosage significantly different between the
two groups (2.4 g with methotrexate and 2.9 g with the placebo). The number of relapses was similar in the two groups
(18 in 10 patients with methotrexate and 15 in 9 patients with
the placebo). In contrast, two other randomized placebocontrolled studies found a decrease in glucocorticoid exposure
in patients given methotrexate [72,73]. The earliest study was
an open-label randomized evaluation of 27 patients [72]. Methotrexate was given intramuscularly in a dosage of 10 mg/week.
Prednisone was started in a dosage of 25 mg/day and tapered
rapidly (25 mg during the first month then 12.5, 10, 6.25, 5,
and 2.5 mg for 1 month each). After 1 year, all patients were in
clinical remission and six patients in the methotrexate group
were off glucocorticoid therapy, compared to none in the placebo group. The mean cumulative glucocorticoid dosage was
significantly lower in the methotrexate group (1.84 g) than in
the placebo group (3.2 g). The other study used a randomized
double-blind placebo-controlled design to evaluate 72 patients,
who were followed up for 18 months [73]. Methotrexate was
given orally in a dosage of 10 mg/week. Patients took 7.5 mg
604
M. Soubrier et al. / Joint Bone Spine 73 (2006) 599–605
of folinic acid orally on the day after each methotrexate dose.
All patients in both groups were treated with prednisone
25 mg/day tapered each month (17.5, 12.5, 7.5, and 5 mg).
Of the 72 patients, 10 (14%) discontinued treatment or were
lost to follow-up. After 76 weeks, 28 (87.5%) of the 32 methotrexate patients compared to only 16 (53%) of the 30 placebo
patients were no longer on prednisone (P=0.003). The relapse
rate was 47% (15/32) in the methotrexate group and 73%
(22/30) in the placebo group. The total number of relapses
was 27 with methotrexate compared to 50 with the placebo
(P=0.009). The mean cumulative prednisone dose was significantly lower in the methotrexate group (2.1 vs. 2.97 g,
P=0.003). In practice, we believe that first-line use of methotrexate, as investigated in these clinical trials, is inappropriate
but that methotrexate may be helpful in patients who are
dependent on or refractory to glucocorticoid therapy. Finally,
a limited amount of data suggests that TNF-α antagonists may
be useful in refractory PMR [74,75]. However, the results of a
randomized double-blind placebo-controlled study of infliximab have tempered the enthusiasm generated by early studies
[76]. The 49 study patients met Healey’s criteria for PMR and
were given 15 mg/day of prednisone. After 16 weeks, the prednisone was stopped and the patients were given either a placebo or infliximab 3 mg/kg at weeks 0, 2, 6, 14, and 22. Evaluations were conducted after 22 and 54 weeks. After
22 weeks, 26 patients were evaluated in the placebo group
and 21 in the infliximab group. No significant differences
were found regarding the remission rate (58% with the placebo
and 48% with infliximab), the duration of prednisone therapy
(18.3 vs. 18.2 weeks), or the glucocorticoid discontinuation
rate (62% vs. 45%).
References
[1]
[2]
Salvarini C, Macchioni P, Boiardi L. PMR. Lancet 1997;350:43–7.
Salvarini C, Cantini F, Boiardi L, Hunder G, Hunder GG. PMR and giant
cell arteritis. N Engl J Med 2002;347:261–71.
[3] Salvarani C, Cantini F, Boiardi L, Hunder GG. PMR. Best Pract Res Clin
Rheumatol 2004;18:705–22.
[4] Nothnagl T, Leeb BF. Diagnosis, differential diagnosis and treatment of
PMR. Drugs Aging 2006;23:309–402.
[5] Salvarini C, Gabriel SE, O’Fallon WM, Hunder GG. Epidemiology of
PMR in Olmsted County, Minnesota, 1970–1991. Arthritis Rheum
1995;38:369–73.
[6] Smeeth L, Cook C, Hall AJ. Incidence of diagnosed PMR and temporal
arteritis in the United Kingdom, 1990–2001. Ann Rheum Dis 2006;65:
1093–8.
[7] Gran JT, Myklebust G. The incidence of PMR and temporal arteritis in
the county of Aust Agder, south Norway: a prospective study 1987–
1994. J Rheumatol 1997;24:1739–43.
[8] Gonzalez-Gay MA, Garcia-Porrua C, Vazquez-Caruncho M, Dababneh
A, Hajeer A, Ollier WE. The spectrum of PMR in northwestern Spain:
incidence and analysis of variables associated with relapse in a 10-year
study. J Rheumatol 1999;26:1326–32.
[9] Doran MF, Crowson CS, O’Fallon WM, Hunder GG, Gabriel SE. Trends
in the incidence of PMR over a 30-year period in Olmsted County, Minnesota, USA. J Rheumatol 2002;29:1694–7.
[10] Cimmino MA, Caporali R, Montecucco CM, Rovida S, Baratelli E,
Broggini MA. Seasonal pattern in the onset of PMR. Ann Rheum Dis
1990;49:521–3.
[11] Elling P, Olsson AT, Elling H. Synchronous variations of the incidence
of temporal arteritis and PMR in different regions of Denmark; association with epidemics of Mycoplasma pneumoniae infection. J Rheumatol
1996;23:112–9.
[12] Cimmino MA, Grazi G, Balistreri M, Accardo S. Increased prevalence of
antibodies to adenovirus and respiratory syncytial virus in PMR. Clin
Exp Rheumatol 1993;11:309–13.
[13] Duhaut P, Bosshard S, Calvet A, Pinede L, Demolombe-Rague S,
Dumontet C, et al. Giant cell arteritis, PMR, and viral hypotheses: a multicenter, prospective case-control study. Groupe de Recherche sur l’Arterite a Cellules Geantes. J Rheumatol 1999;26:361–9.
[14] Narvaez J, Clavaguera MT, Nolla-Sole JM, Valverde-Garcia J, RoigEscofet D. Lack of association between infection and onset of PMR. J
Rheumatol 2000;27:953–7.
[15] Peris P. PMR is not seasonal in pattern and is unrelated to parvovirus 19
infection. J Rheumatol 2003;30:2624–6.
[16] Haworth S, Ridgeway J, Stewart I, Dyer PA, Pepper L, Ollier W. PMR is
associated with both HLA-DRB1*0401 and DRB1*0404. Br J Rheumatol 1996;35:632–5.
[17] Salvarani C, Boiardi L, Mantovani V, Ranzi A, Cantini F, Olivieri I,
et al. HLA-DRB1 alleles associated with PMR in northern Italy: correlation with disease severity. Ann Rheum Dis 1999;58:303–8.
[18] Cutolo M, Straub RH, Foppiani L, Prete C, Pulsatelli L, Sulli A, et al.
Adrenal gland hypofunction in active PMR. effect of glucocorticoid treatment on adrenal hormones and interleukin 6. J Rheumatol 2002;29:748–
56.
[19] Straub RH, Cutolo M. Further evidence for insufficient hypothalamicpituitary-glandular axes in PMR. J Rheumatol 2006;33:1219–23.
[20] Narvaez J, Bernad B, Torne CD, Momplet JV, Montpel JZ, Nolla JM,
et al. Low Serum Levels of DHEAS in Untreated PMR/Giant Cell Arteritis. J Rheumatol 2006;33:1293–8.
[21] Salvarani C, Cantini F, Macchioni P, Olivieri I, Nicoli L, Padula A, et al.
Distal musculoskeletal manifestations in PMR: a prospective followup
study. Arthritis Rheum 1998;41:1221–6.
[22] Cantini F, Salvarani C, Olivieri I, Macchioni L, Ranzi A, Niccoli L, et al.
Erythrocyte sedimentation rate and C-reactive protein in the evaluation of
disease activity and severity in PMR: a prospective follow-up study.
Semin Arthritis Rheum 2000;30:17–24.
[23] Proven A, Gabriel SE, O’Fallon WM, Hunder GG. PMR with low erythrocyte sedimentation rate at diagnosis. J Rheumatol 1999;26:1333–7.
[24] Helfgott SM, Kieval RI. PMR in patients with a normal erythrocyte sedimentation rate. Arthritis Rheum 1996;39:304–7.
[25] Gonzalez-Gay MA, Rodriguez-Valverde V, Blanco R, Fernandez-Sueiro
JL, Armona J, Figueroa M, et al. PMR without significantly increased
erythrocyte sedimentation rate. A more benign syndrome. Arch Intern
Med 1997;157:317–20.
[26] Weyand CM, Fulbright JW, Evans JM, Hunder GG, Goronzy JJ. Corticosteroid requirements in PMR. Arch Intern Med 1999;159:577–84.
[27] Salvarani C, Cantini F, Niccoli L, Macchioni P, Consonni D, Bajocchi G,
et al. Acute-phase reactants and the risk of relapse/recurrence in PMR: a
prospective followup study. Arthritis Rheum 2005;53:33–8.
[28] Salvarani C, Cantini F, Olivieri I, Barozzi L, Macchioni L, Niccoli L,
et al. Proximal bursitis in active PMR. Ann Intern Med 1997;127:27–31.
[29] Cantini F, Salvarani C, Olivieri I, Niccoli L, Padula A, Macchioni L,
et al. Shoulder ultrasonography in the diagnosis of PMR: a case-control
study. J Rheumatol 2001;28:1049–55.
[30] Falsetti P, Fredniani B, Storri L, Bisogno S, Baldi F, Campanella V,
et al. Evidence for synovitis in active PMR: sonographic study in a
large seriesof patients. J Rheumatol 2002;29:123–30.
[31] Cantini F, Salvarani C, Olivieri I, Barozzi L, Macchioni L, Niccoli L,
et al. Remitting seronegative symmetrical synovitis with pitting oedema
(RS3PE) syndrome: a prospective follow up and magnetic resonance
imaging study. Ann Rheum Dis 1999;58:230–6.
[32] Bird HA, Esselinckx W, Dixon AS, Mowat AG, Wood PH. An evaluation of criteria for PMR. Ann Rheum Dis 1979;38:434–9.
M. Soubrier et al. / Joint Bone Spine 73 (2006) 599–605
[33] Bird HA, Leeb BF, Montecucco CM, Misiuniene N, Nesher G, Pai S,
et al. A comparison of the sensitivity of diagnostic criteria for PMR.
Ann Rheum Dis 2005;64:626–9.
[34] Chuang TY, Hunder GG, Ilstrup DM, Kurland LT. PMR: a 10-year epidemiologic and clinical study. Ann Intern Med 1982;97:672–80.
[35] Healey LA. Long-term follow-up of PMR: evidence for synovitis. Seminar Arthritis Rheum 1984;13:322–8.
[36] Gonzalez-Gay MA, Garcia-Porrua C, Salvarini C, Olivieri I, Hunder GG.
The spectrum of conditions mimicking PMR in northwestern Spain. J
Rheumatol 2000;27:2179–84.
[37] Blockmans D, Stroobants S, Maes A, Mortelmans L. Positron emission
tomography in giant cell arteritis and PMR: evidence for inflammation of
the aortic arch. Am J Med 2000;108:246–9.
[38] Blockmans D, de Ceuninck L, Vanderschueren S, Knockaert D, Mortelmans L, Bobbaers H. Repetitive 18F-Fluorodeoxyglucose positron emission emission tomography in giant cell arteritis: a prospective study of 35
patients. Arthritis Rheum 2006;55:131–7.
[39] Blockmans D, de Ceuninck L, Vanderschueren S, Knockaert D, Mortelmans L, Bobbaers H. Repetitive 18F-Fluorodeoxyglucose positron emission tomography in isolated PMR: a prospective study of 35 patients.
Ann Rheum Dis 2006;65(Suppl 11):366.
[40] Reitblat T, Ben-Horin CL, Reitblat A. Gallium-67 SPECT scintigraphy
may be useful in diagnosis of temporal arteritis. Ann Rheum Dis 2003;
62:257–60.
[41] Reitblat T, Ben-Horin CL, Reitblat A. Increased 67gallium uptake among
PMR patients. Is it additional evidence of its vasculitic nature? Rheumatol Int 2006;26(11):1010–3.
[42] Schmidt WA, Gromnica-Ihle E. Incidence of temporal arteritis in patients
with PMR: a prospective study using colour Doppler ultrasonography of
the temporal arteries. Rheumatol 2002;41:46–52.
[43] Van der Heijde DMFM, van Riel PLCM, van Leeuwen MA, van’t
Hof MA, van Rijswijk MH, van de Putte LBA. Older versus younger
onset rheumatoid arthritis: results at onset and after 2 years of a prospective follow-up study of early rheumatoid arthritis. J Rheumatol 1991;18:
1285–9.
[44] Pease CT, Bhakta BB, Devlin J, Emery P. Does the age of onset of rheumatoid arthritis influence phenotype? A prospective study of outcome
and prognostic factors. Rheumatol 1999;38:228–34.
[45] Van Schaardenburg D, Breedveld FC. Elderly-onset rheumatoid arthritis.
Sem Arthritis Rheum 1994;23:367–78.
[46] Lopez-Hoyos M, Ruiz de Alegria C, Blanco R, Crespo J, Pena M,
Rodriguez-Valverde V, et al. Clinical utility of anti-CCP antibodies in
the differential diagnosis of elderly-onset rheumatoid arthritis and PMR.
Rheumatol 2004;43:655–7.
[47] Ceccato F, Roverano S, Barrionuevo A, Rillo O, Paira S. The role of
anticyclic citrullinated peptide antibodies in the differential diagnosis of
elderly-onset rheumatoid arthritis and polymyalgia rheumatica. Clin
Rheumatol 2006;25(6):854–7.
[48] Pease CT, Haugeberg G, Morgan AW, Montague B, Hensor EM,
Bhakta BB. Diagnosing late onset rheumatoid arthritis, PMR, and temporal arteritis in patients presenting with polymyalgic symptoms. A prospective longterm evaluation. J Rheumatol 2005;32:1043–6.
[49] Olive A, del Blanco J, Pons M, Vaquero M, Tena X. The clinical spectrum of remitting seronegative symmetrical synovitis with pitting edema.
The Catalan Group for the Study of RS3PE. J Rheumatol 1997;24:333–
6.
[50] Dubost JJ, Sauvezie B. Late onset peripheral spondylarthropathy. J Rheumatol 1989;16:214–7.
[51] Hutton CW, Maddison PJ. Systemic lupus erythematosus presenting as
polymyalgia in the elderly. Ann Rheum Dis 1986;45:641–4.
[52] Boddaert J, Huong du LT, Amoura Z, Wechsler B, Godeau P, Piette JC.
Late-onset systemic lupus erythematosus. A personal series of 47 patients
and pooled analysis of 714 cases in the literature. Medicine 2004;83:48–
59.
[53] Pego-Reigosa JM, Rodriguez-Rodriguez M, Hurtado-Hernandez Z,
Gromaz-Martin J, Taboas-Rodriguez D, Millan-Cachinero C, et al. Calcium pyrophosphate deposition disease mimicking PMR: a prospective
[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
605
followup study of predictive factors for this condition in patients presenting with polymyalgia symptoms. Arthritis Rheum 2005;53:931–8.
Dubost JJ, Soubrier M, Sauvezie B. Le syndrome inflammatoire manquant. Presse Med 1992;21:755–8.
Goëb V, Guillemant N, Vittecoq O, Le Loët X. Cerivastatin-induced
PMR-like disease. Clin Rheum 2004;23:179.
Snyder S. Metoprolol-induced polymyalgia-like syndrome. Ann Intern
Med 1991;114:96–7.
Chassagne P, Mejjad O, Noblet C, Gourmelen O, Moore N, Le Loet X,
et al. PseudoPMR with dipyridamole. BMJ 1990;301(6756):875.
Le Loet X, Moore N, Deshayes P. PseudoPMR during treatment with
enalapril. BMJ 1989;298(6669):325.
Gonzalez-Juanatey C, Gonzalez-Gay MA, Llorca J, Crespo F, GarciaPorrua C, Corredoira J, et al. Rheumatic manifestations of infective endocarditis in non-addicts. A 12-year study. Medicine (Baltimore) 2001;80:
9–19.
Soubrier M, Dubost JJ, Fournier P, Mallochet S, Ristori JM. Rhizomelic
pseudopolyarthritis: initial manifestation of a myelodysplasia. Rev Med
Interne 2002;23:673.
Lafforgue P, Senbel E, Figarella-Branger D, Boucraut J, Horschowsky N,
Pellissier JF, et al. Systemic amyloidosis AL with temporal artery involvement revealing lymphoplasmacytic malignancy in a man presenting as
PMR. Ann Rheum Dis 1993;52:158–60.
Myklebust G, Wilsgaard T, Jacobsen BK, Gran JT. No increased frequency of malignant neoplasms in PMR and temporal arteritis. A prospective longitudinal study of 398 cases and matched population controls. J Rheumatol 2002;29:2143–7.
Gabriel SE, Sunku J, Salvarni C, O’Fallon WM, Hunder GG. Adverse
outcomes of anti-inflammatory therapy among patients with PMR.
Arthritis Rheum 1997;40:1873–8.
Kremers HM, Reinalda MS, Crowson CS, Zinsmeister AR, Hunder GG,
Gabriel SE. Relapse in a population based cohort of patients with PMR. J
Rheumatol 2005;32:65–73.
Leeb BF, Bird HA. A disease activity score for PMR. Ann Rheum Dis
2004;63:1279–83.
Li C, Dasgupta B. Corticosteroids in PMR—a review of different treatment schedules. Clin Exp Rheumatol 2000;18(Suppl):56–7.
Salvarani C, Cantini F, Olivieri I, Barozzi L, Macchioni L, Boiardi L,
et al. Corticosteroid injections in PMR: a double blind, prospective, randomized, placebo controlled study. J Rheumatol 2000;27:1470–6.
David-Chausse J, Dehais J, Leman A. Résultats d’une enquête régionale
sur le traitement de la pseudopolyarthrite rhizomélique et de l’artérite
temporale. Rev Rhum 1983;50:563–71.
Wagener P. Methotrexate therapy of PMR. Z Rheumatol 1995;54:413–6.
Feinberg HL, Sherman JD, Schrepferman CG, Dietzen CJ, Feinberg GD.
The use of methotrexate in PMR. J Rheumatol 1996;23:1550–2.
Van der Veen MJ, Dinant HJ, van Booma-Frankfort C, van AlbadaKuipers GA, Bijlsma JW. Can methotrexate be used as a steroid sparing
agent in the treatment of PMR and giant cell arteritis? Ann Rheum Dis
1996;55:218–23.
Ferraccioli G, Salaffi F, De Vita S, Casatta L, Bartoli E. Methotrexate in
PMR: preliminary results of an open, randomized study. J Rheumatol
1996;23:624–8.
Caporali R, Cimmino MA, Ferracioli G, Gerli R, Klersy C, Salvarani C,
et al. for the systemic vasculitis study group of the Italian society for
rheumatology. Prednisone plus Methotrexate for PMR. A randomized,
double-blind, placebo-controlled trial. Ann Intern Med 2004;141:493–
500.
Salvarani C, Cantini F, Niccoli L, Catanoso MG, Macchioni P, Pulsatelli
L, et al. Treatment of refractory PMR with infliximab: a pilot study. J
Rheumatol 2003;30:760–3.
Cattanoso M, Macchioni P, Boiardi L, Salvarani C. TNF-alpha blockade
with etanercept in patients with refractory PMR and steroid related
adverse events. Ann Rheum Dis 2006;65(Suppl):367.
Salvarani C, Manzini C, Paolazzi G, Trotta A, Manganelli P, Cimmino
M, et al. Infliximab in the treatment of PMR: a double blind randomized
placebo controlled study. Arthritis Rheum 2005;52(Suppl):S676.