To assess the characteristics of calcium pyrophosphate deposition disease (CPDD) with proximal involvement mimicking polymyalgia rheumatica (PMR), and to identify the best predictive factors for the presence of a clinical pattern of CPDD in patients presenting with polymyalgia symptoms.
Patients diagnosed with either PMR or CPDD at the Rheumatology Division of Hospital Meixoeiro (Vigo, Spain) over a 7-year period (1997–2003) were prospectively followed for at least 12 months.
The study group comprised 118 patients with PMR features and 112 patients with CPDD. Eighty-two of the 118 patients with PMR manifestations were diagnosed as having pure PMR, and 36 met the diagnostic criteria for both PMR and CPDD. Patients with CPDD mimicking PMR were older (P = 0.02) and had peripheral arthritis more frequently (P = 0.004) than those with pure PMR. Radiologic osteoarthritic changes in the hands and knees, including more advanced radiologic grade of knee osteoarthritis, and tendinous calcifications were more frequent in patients with PMR/CPDD (P < 0.001). The best predictive factors for the occurrence of this atypical pattern of CPDD in a patient presenting with PMR features were the age at diagnosis and the presence of tibiofemoral osteoarthritis, tendinous calcifications, and ankle arthritis.
Involvement of proximal joints may be the clinical presentation of CPDD. CPDD should be included in the spectrum of diseases mimicking PMR. The presence of tibiofemoral osteoarthritis, tendinous calcifications, and ankle arthritis are clues that may alert the clinician to the presence of CPDD in an elderly patient presenting with PMR manifestations.
A variable proportion of patients with calcium pyrophosphate deposition disease (CPDD) may present with proximal involvement. However, to the best of our knowledge, the prevalence of CPDD mimicking polymyalgia rheumatica (PMR) has not been well established. Our results support that CPDD with PMR symptoms is not exceptional. The presence of tibiofemoral osteoarthritis, tendinous calcifications, and ankle arthritis are clues that may alert the clinician to the presence of CPDD in an elderly patient presenting with PMR manifestations.
CPDD is a common disorder in the elderly. Clinical manifestations may vary, but 5 classic presentations have been previously described: asymptomatic, acute pseudogout, pseudorheumatoid arthritis, pseudoosteoarthritis, and pseudoneuropathic joint disease, to which other forms were later added (1, 2). Every joint can be involved, and when the neck, shoulders, and hips are affected, the clinical picture can resemble PMR (3, 4).
To accurately examine the frequency; characteristic clinical, laboratory, and radiologic features; and outcome of CPDD with predominant proximal involvement, we prospectively followed a series of consecutive patients meeting inclusion criteria for either PMR (5, 6) or CPDD (definite or probable disease) (7). We compared the findings observed in our patients with both PMR features and CPDD criteria (PMR/CPDD patients) with those of patients presenting with only PMR features (pure PMR patients) to try to identify the best predictive factors for the diagnosis of CPDD.
PATIENTS AND METHODS
Patients and inclusion criteria.
Patients diagnosed as having either PMR (according to the criteria proposed by Chuang et al  and Healey ) or CPDD (according to the revised criteria of McCarty [2, 7]) at the Rheumatology Division of Hospital Meixoeiro (Vigo, Spain) over a 7-year period (1997–2003) were prospectively followed for at least 12 months. Patients were diagnosed as having definite CPDD if calcium pyrophosphate dihydrate crystals were identified by compensated polarized light microscopy, and if typical radiographic calcifications (chondrocalcinosis) were also observed. When only 1 of these 2 criteria was present, patients were diagnosed as having probable CPDD.
Hospital Meixoeiro is the single rheumatology referral center for a white population of almost 200,000 persons living in and around Vigo city, in Galicia, Northwestern Spain. Patients initially diagnosed as having PMR who fulfilled the American College of Rheumatology (ACR) classification criteria for rheumatoid arthritis (8) during their followup were excluded. Patients presenting with PMR symptoms associated with well-defined diseases other than giant cell arteritis (GCA), such as infections or tumors, which could have explained the PMR manifestations, were also excluded (9, 10).
Data collection and management.
Patients were evaluated by the same rheumatologists (JMP or IHR) at diagnosis and then once per month for the first 3 months. Afterwards, they were seen every 3 months at the rheumatology outpatient clinic during the followup period.
A specifically designed protocol was used to register information at diagnosis, including age, sex, associated conditions (metabolic diseases such as hyperuricemia and/or gout; hemochromatosis; ochronosis or Wilson's disease; endocrinopathies including hypothyroidism and hyperparathyroidism; infections; neurologic diseases; rheumatic conditions including connective tissue diseases; tumors; and vasculitides, in particular GCA), location of pain and stiffness, delay in the diagnosis, fever, and presence of synovitis and its location. At diagnosis and then at each visit, erythrocyte sedimentation rate (ESR, Westergren method), C-reactive protein (CRP, by nephelometry), hemoglobin, platelet count, and liver enzyme levels were determined. At diagnosis, serum protein electrophoresis and rheumatoid factor were also performed. Synovial fluid was analyzed in 12 of the patients with PMR manifestations who presented with peripheral arthritis. Plain radiographs of the hands, pelvis, and/or knees were performed if local symptoms were reported by the patient or if joint physical examination was considered abnormal by the physician. All patients who were diagnosed with PMR/CPDD underwent either synovial fluid analysis or plain radiographs, or both.
Cumulative dose of corticosteroids, duration of the disease, and incidence of relapses or recurrences and their characteristics were also recorded. A relapse was defined as an increase in the musculoskeletal manifestations that occurred <1 month after reduction or discontinuation of treatment. Recurrence was defined as the presence of new musculoskeletal manifestations occurring >1 month after treatment had been completed (11). The end of the disease was considered when therapy could be discontinued without relapse or recurrence. As discussed before, all patients included in this study were required to have been followed for at least 12 months after diagnosis.
Continuous and categorical variables were described as mean ± SD and percentages, respectively. Comparisons between PMR/CPDD patients and pure PMR patients were performed using Student's t-test for continuous variables and the chi-square test for categorical variables. When the minimum expected value was <5, Fisher's exact test was used. Laboratory data observed at diagnosis were compared with those found at 1 month and at 12 months using Student's paired t-test. To identify the best predictive variables for the diagnosis of PMR/CPDD in patients presenting with polymyalgia symptoms, a logistic regression analysis was performed. Statistical significance was set at the 5% level. Data were analyzed using SPSS for Windows (release 11.5; SPSS, Chicago, IL).
The study group comprised 118 patients with PMR features who fulfilled the classification criteria proposed by Chuang et al (5) and Healey (6) and 112 patients diagnosed with CPDD according to the modified criteria of McCarty (2, 7). Of these, 36 patients met diagnostic criteria for both PMR and CPDD (5 met criteria for definite CPDD and 31 met the criteria for probable CPDD). The remaining 82 patients with PMR manifestations were diagnosed as having pure PMR. Eleven patients were also diagnosed as having GCA according to the 1990 ACR classification criteria (12).
Differences between patients with PMR/CPDD and those with pure PMR are shown in Table 1. The age at disease diagnosis and the occurrence of GCA were significantly different between both groups. Prior to the onset of PMR symptoms, 2 patients diagnosed with pure PMR had been diagnosed with hypothyroidism. This disorder was not considered to be responsible for the PMR features because the patients were diagnosed with hypothyroidism several years before the onset of PMR. In addition, both patients had a euthyroid status for >2 years before the diagnosis of PMR and experienced dramatic improvement of PMR symptoms <48 hours after the onset of prednisone therapy. Peripheral synovitis was more commonly observed in PMR/CPDD patients (Table 1).
Table 1. Comparative analysis of clinical data between patients with PMR/CPDD and pure PMR*
The laboratory test results at the time of diagnosis are shown in Table 2. Liver test abnormalities were found in 19.4% of PMR/CPDD patients and in 13.4% of pure PMR patients (P not significant). A cholestatic pattern with mild elevation of alkaline phosphatase and gamma-glutamyl transpeptidase was the most common hepatic abnormality in PMR/CPDD patients. No specific pattern was seen in the group of patients with pure PMR.
Table 2. Comparative analysis of analytical data between patients with PMR/CPDD and pure PMR*
Serum protein electrophoresis abnormalities were significantly more frequent in PMR/CPDD patients compared with pure PMR patients (P = 0.01). An electrophoretic pattern suggesting the presence of an inflammatory process (mild hypoalbuminemia and elevated alpha-1 and alpha-2 globulins) was seen in nearly 50% of the PMR/CPDD patients. Polyclonal hypergammaglobulinemia and monoclonal gammopathy of unknown origin were seen more frequently in patients with pure PMR.
Synovial fluid analyses were performed in 12 patients, 8 patients with PMR/CPDD and 4 with pure PMR. The presence of calcium pyrophosphate dihydrate established the diagnosis of crystal deposition disease in 7 of the 8 PMR/CPDD patients. No crystals were observed in the 4 patients diagnosed with pure PMR.
The types of radiologic manifestations in the patients of both groups are summarized in Table 3. Osteoarthritic changes in tibiofemoral and patellofemoral joints were significantly more frequent in PMR/CPDD patients (P < 0.001). Moreover, PMR/CPDD patients had a more advanced radiologic severity of knee osteoarthritis according to the Kellgren-Lawrence grading system (13) (13 of 36 presented with grade III or IV radiologic changes).
Table 3. Comparative analysis of radiologic data between patients with PMR/CPDD and pure PMR*
Values are the number (percentage). PMR/CPDD = polymyalgia rheumatica/calcium pyrophosphate deposition disease.
Thirty-four patients were studied.
Sixty-two patients were studied.
All PMR/CPDD patients received treatment with prednisone (or equivalent dose) at an initial dosage of 10–20 mg/day (median 15 mg). Of these patients, 32 (88.9%) had a rapid clinical response to treatment with steroids in <72 hours. Apart from the 11 patients who had PMR associated with GCA (who were initially treated with 40 mg of prednisone per day), the patients with pure PMR were successfully treated with an initial dosage of 10–20 mg of prednisone per day (median 15 mg).
Acute phase reactants decreased rapidly in a few days after the onset of steroid therapy in patients from both groups. When basal data were compared with data at 1 month and then at 12 months, significant differences were seen. In this regard, in the PMR/CPDD group the mean ESR decreased from 72.9 mm/hour at diagnosis to 31.6 mm/hour at 1 month and 28.6 mm/hour at 12 months (P < 0.001 for both comparisons). Likewise, in this group the mean CRP level decreased from 50.6 mg/liter at diagnosis to 5.3 mg/liter at 1 month and 6.1 mg/liter at 12 months (P < 0.001 for both comparisons). Also, in PMR/CPDD patients the mean platelet count was 295,000/mm3 at diagnosis, 218,000/mm3 at 1 month, and 240,000/mm3 at 12 months (P < 0.001 for both comparisons). Finally, in this group of PMR/CPDD patients a significant increase of hemoglobin was observed following treatment (mean hemoglobin at diagnosis 12.4 gm/dl, 13.1 gm/dl at 1 month, and 13.5 gm/dl at 12 months; P < 0.05 for both comparisons). Similar improvement in the acute phase reactants and hemoglobin values was observed following corticosteroid therapy in the group of pure PMR patients (data not shown).
Three (8.3%) of the 36 PMR/CPDD patients experienced a relapse of the symptoms. Nine (24.9%) patients had a recurrence of the disease that occurred in a period ranging between 5 and 50 months after the discontinuation of the steroid therapy. Three of these patients had ≥2 recurrences. The mean ± SD period from the disease diagnosis to recurrence was 22.3 ± 17.1 months. Proximal involvement was present in all the recurrences. Nine (11.1%) of the 82 patients with pure PMR experienced a relapse of the symptoms. Also, 31 (37.8%) patients with pure PMR had a recurrence of the disease that occurred in a period ranging between 1 and 44 months after discontinuation of corticosteroid therapy. Seven of these patients experienced ≥2 recurrences. However, no statistically significant differences were observed in the frequency of the relapses or recurrences between PMR/CPDD and pure PMR patients.
In the PMR/CPDD group, the mean ± SD duration of treatment was 19.8 ± 19.7 months, and the mean ± SD cumulative dose of prednisone (or equivalent dose) was 5,479 ± 11,566 mg. At the end of the study, 11 of the 36 patients still required low dosages of prednisone (≤5 mg/day) or nonsteroidal antiinflammatory drugs to control symptoms. In patients with pure PMR, the mean ± SD duration of treatment was 26.3 ± 30.9 months and the mean ± SD cumulative dose of prednisone was 6,275 ± 17,146 mg. Although these values were higher in the latter group, no significant differences in terms of duration of treatment and cumulative dose of prednisone between both groups were found.
By multivariate analysis, we found that in addition to older age, the best predictive model for the diagnosis of this atypical clinical form of CPDD in a patient presenting with PMR symptoms included the presence of tibiofemoral osteoarthritis, tendinous calcifications, and arthritis in the ankles (Table 4). Twenty-eight (77.7%) of the 36 PMR/CPDD patients and only 27 (32.9%) of the 82 pure PMR patients had ≥1 of these 3 latter predictive factors for the occurrence of this atypical clinical pattern of CPDD. Thirteen (36.1%) of the 36 patients from the first group had at least 2 of these 3 predictive factors, whereas only 1 (1.2%) of the 82 patients with pure PMR had at least 2 predictive factors. As shown in the receiver operating characteristic curve (Figure 1), the area under the curve was 0.845. For a cutoff point of 0.5, the sensitivity was 55.9%, specificity was 92.9%, positive predictive value was 76%, and negative predictive value was 83%.
Table 4. Predictive variables for the diagnosis of CPDD in patients presenting with PMR symptoms*
95% CI for OR
CPDD = calcium pyrophosphate deposition disease; PMR = polymyalgia rheumatica; OR = odds ratio; 95% CI = 95% confidence interval.
Age at diagnosis, years
This study was performed to better define the characteristics of CPDD involving predominantly proximal joints. Little is known about this atypical clinical presentation of the disease. Dieppe and colleagues reported 8 individuals with presumed PMR from a series of 105 patients with pyrophosphate arthropathy, suggesting that either CPDD might present with polymyalgic symptoms or that the steroid treatment prescribed to these patients with PMR features might predispose to the development of chondrocalcinosis (3). More recently, 3 patients with crowned dens syndrome (association of radiologic calcification of the cruciform ligament around the odontoid process and acute cervico-occipital pain with fever, neck stiffness, and biologic inflammatory syndrome) and chondrocalcinosis of the wrist and knee who were misdiagnosed as having PMR have been described (4). However, to the best of our knowledge, a prospective study on a large series of patients who meet the diagnostic criteria for CPDD (7) and PMR manifestations (5, 6) has not been reported.
In an effort to make an accurate description of this condition, we assessed our community cohort of 118 patients with PMR features according to the criteria proposed by Chuang et al (5) and Healey (6) and 112 patients diagnosed as having CPDD according to the revised criteria of McCarty (2, 7) who had been diagnosed and followed for at least 1 year over a 7-year period. In our series, predominant proximal symptoms occurred in 36 (32.1%) of the 112 patients with CPDD. This is a high proportion if we consider the 5 classic patterns of CPDD that were described 4 decades ago: asymptomatic, acute pseudogout, pseudorheumatoid arthritis, pseudoosteoarthritis, and pseudoneuropathic joint (1). McCarty reported CPDD resembling other conditions such as traumatic arthritis, ankylosing spondylitis, rheumatic fever, or psychogenic arthritis (2). Later, other unusual presentations were described (Table 5).
Table 5. Atypical presentations of calcium pyrophosphate dihydrate deposition disease*
The relatively large numbers of patients diagnosed with CPDD mimicking PMR in our prospective study allowed us to offer a way to compare this condition with pure PMR. PMR typically affects elderly persons, and an age of >50 years is a criterion for PMR (5, 6). CPDD also is a common age-related disorder. However, in our study patients with PMR/CPDD were significantly older than those with pure PMR, with a mean age difference of 4.3 years between both groups (P = 0.02). Also, in the multivariate study (32) described in the present study, age remained a statistically significant variable, with an odds ratio of 1.088 per year.
Familial predisposition and associated metabolic disorders (33) are rare findings in CPDD, although each one may be linked with an earlier age at presentation. Neither familial nor metabolic predisposition was observed in the majority of our patients with CPDD. Our results disclosed a significantly higher prevalence of peripheral arthritis in patients with PMR/CPDD compared with those patients with pure PMR (P = 0.004). Furthermore, the evidence of ankle arthritis in a patient presenting with polymyalgia symptoms was a predictive factor for the diagnosis of this pseudo-PMR pattern of CPDD. In this regard, 14 (38.9%) of the 36 patients in our series diagnosed with PMR/CPDD had peripheral arthritis. Most of them presented with peripheral arthritis and polymyalgia symptoms simultaneously. Peripheral arthritis involving the ankle preceded PMR manifestations in only 1 patient with PMR/CPDD. This episode occurred 4 years prior to the onset of PMR symptoms, and calcium pyrophosphate dihydrate crystals were identified in the synovial fluid. In approximately one-fifth of the PMR/CPDD patients, the wrist and the ankle were the most commonly involved joints. We observed involvement of the metatarsophalangeal joints in 4 patients, always at the same time as the proximal symptoms.
Only 11 (13.4%) of the 82 patients diagnosed as having pure PMR had peripheral arthritis. In contrast to our observations, Salvarani and coworkers (34) reported peripheral arthritis in 45 (25%) of 177 patients meeting clinical criteria for PMR. Both the knees and the wrists were affected in 40% of the episodes (34). However, in concordance with our present observations, Gonzalez-Gay and colleagues found that peripheral synovitis was also uncommonly reported in patients from another region of Northwest Spain with isolated PMR or with PMR associated with GCA (35).
From a radiologic point of view, it is noteworthy that there was a significantly higher frequency of osteoarthritis of the hands and knees (both tibiofemoral and patellofemoral) in our patients that presented with polymyalgia symptoms and met the criteria for CPDD compared with those with pure PMR. Of the patients with PMR/CPDD, 47.2% presented with hand osteoarthritis and 72.2% presented with knee osteoarthritis at the time of the onset of PMR symptoms, compared with only 13.4% and 30.5% of patients with pure PMR, respectively (P < 0.001 for both comparisons). In addition, the presence of tibiofemoral osteoarthritis in a patient presenting with polymyalgia symptoms was a predictive factor for the diagnosis of this atypical clinical pattern of CPDD. A tendinous calcification was also significantly more common in the group of PMR/CPDD patients (27.8% versus 2.4%, P < 0.001), which was another predictive factor for the diagnosis of PMR/CPDD. The most common locations of tendinous calcifications were the rotator cuff tendons and the quadriceps tendon. In our patients, this tendinous calcium deposition was always diagnosed by a plain radiograph. Considering that these 2 more commonly affected areas are very accessible for the ultrasonographic assessment, this technique may be useful in the detection of tendinous calcifications. Moreover, because the usefulness of the echographic methods for the evaluation of the patients with polymyalgia symptoms has been clearly demonstrated (36, 37), we think that ultrasonography should be considered as a possible tool in the diagnosis of PMR and even CPDD.
According to the diagnostic criteria proposed by Chuang et al (5) and Healey (6) for PMR, apart from GCA, other diseases capable of causing musculoskeletal symptoms must be excluded. In this regard, a wide variety of diseases can mimic PMR (9, 10, 38), such as malignant neoplasms (hematologic [10, 38–40] or solid tumors [10, 38, 41–43]), infectious diseases (bacterial endocarditis [10, 38, 44]), rheumatic conditions (rheumatoid arthritis [38, 45], systemic lupus erythematosus [10, 38, 46], polymyositis [38, 47], vasculitis [48, 49], amyloidosis , and ankylosing spondylitis [38, 50]), and some other disorders (hypothyroidism , Parkinson's syndrome , and fibromyalgia ). In our study, we reported a large series of patients with pain and stiffness involving the neck, the shoulder, and/or the pelvic girdles that were diagnosed as having CPDD by the identification of calcium pyrophosphate dihydrate crystals in the synovial fluid and/or by typical radiographic findings (chondrocalcinosis). Therefore, our study provides clues that support the inclusion of CPDD in the spectrum of diseases resembling PMR.
In summary, an important concern for the clinician may be to distinguish elderly patients with pure PMR from others presenting with polymyalgia symptoms resembling this condition. According to our observations, CPDD must be included in the wide spectrum of diseases mimicking PMR. Tibiofemoral osteoarthritis, tendinous calcifications, and ankle arthritis in an elderly patient are the variables that may better predict that a patient with PMR features may have an atypical clinical pattern of CPDD.