Clinical manifestations of polymyalgia rheumatica – a single centre experience

INTRODUCTION

Polymyalgia rheumatica (PMR) is a chronic inflammatory rheumatic disease manifested by pain in the shoulder and pelvic girdle and neck, morning stiffness, and increased acute phase reactants such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Joint effusion is often present in shoulder and hip joints. This disease most commonly occurs in people over the age of 50 and its incidence increases with ageing (1, 2).

Approximately 10 – 16% of PMR patients develop giant cell arteritis (GCA) (3). This is the most common form of large blood vessel vasculitis which predominantly affects the extracranial branches of the carotid arteries and aorta, and is followed by symptoms such as headache, fever and / or vision loss (3, 4). A clear aetiology of PMR is yet to be defined, but it is thought that the main cause of immune system modulation is associated with ageing in genetically predisposed individuals (3, 5). Given that the incidence of PMR increases in old age, when the incidence of malignancy also increases, PMR has long been considered part of paraneoplastic syndromes, but this has not been clearly confirmed (6–8).

One of the characteristics of this disease is an excellent therapeutic response to low doses of glucocorticoids (GC).

The aim of this study was to determine the clinical manifestations of PMR in patients treated at the Division of Rheumatology and Clinical Immunology of the Split University Hospital Centre, the frequency and type of comorbidities and the response to the therapy used.

SUBJECTS AND METHODS

The study included patients with a clear diagnosis of PMR in accordance with the 2012 EULAR / ACR classification criteria, who were treated at the Division of Rheumatology and Clinical Immunology, Split University Hospital Centre (9).

We analysed available medical records of patients who have received outpatient or inpatient care in the period from January 2015 to July 2020. Apart from the demographic data, the manifestations of the disease and its duration were recorded as well. In addition to that, comorbidities and the occurrence of malignant neoplasms were recorded, as well as symptoms that would indicate the occurrence of GCA. The therapy used in the treatment of patients, the response to therapy used, the number of patients in remission, the number of patients who have experienced relapse and the number of patients with active disease were analysed. Methods of descriptive statistics were used in the analysis. The collected data were analysed in Microsoft Excel.

RESULTS

The study included 49 PMR patients. Out of the total number of patients, 33 (67.35%) were female and 16 (32.65%) were male. The mean age of patients was 77, ranging from 62 to 92, and the mean age at diagnosis was 74.5. The mean age for the diagnosis of PMR was 76 for women, and 71.5 for men. The cohort analysis revealed that the average duration of the disease was 2.5 years, with the average duration of the disease being slightly longer in women (2.79 years) than in men (1.88 years).

PMR manifested as joint pain in 91.84% of patients, fever (37.5 °C, axillary temperature) in 28.57% of patients, while headaches were recorded in 18.37% of patients (Figure 1). At the time of diagnosis, all patients reported pain and stiffness in the shoulders and shoulder girdle muscles, while 33 patients (67.4%) reported pain and stiffness in the hips and pelvic girdle muscles. Hand pain was recorded in 18 patients (36.7%), and knee pain was recorded in 13 patients (26.5%). A total of 43 patients (87.8%) reported significant morning stiffness lasting over 30 minutes. The headaches reported did not have GCA-specific characteristics, and patients with early-onset headaches did not meet the GCA criteria. None of the patients had positive antibodies to citrullinated proteins, while rheumatoid factor was detected in low titre in four patients (8.2%). Regarding the values of inflammatory parameters, the average value of erythrocyte sedimentation rate (ESR) at the time of diagnosis was 61 ± 25 mm/hr, and the average value of CRP was 74 ± 61.7 mg/dl. After treatment with low doses of glucocorticoids, the values decreased significantly and the average value of the last recorded ESR was 18 ± 13 mm/hr, and CRP 7.7 ± 4.4 mg/dl. As part of the diagnosis of PMR, ultrasound examination of the shoulder joints was performed in 10 patients (20.4%). The most common comorbidities were arterial hypertension, found in 73.47% of cases, type 2 diabetes, found in 38.78% of cases, and various heart diseases such as ischemic or dilated cardiomyopathy, found in 36.73% of cases (Figure 2). Osteoporosis was recorded in 8 patients (16.33%). When it comes to concomitant inflammatory rheumatic diseases, GCA was diagnosed in 6 patients through additional diagnostic processing, while seronegative polyarthritis was diagnosed in three patients, rheumatoid arthritis was diagnosed in one patient and generalised osteoarthritis was diagnosed in one patient as well. Most cases of concomitant inflammatory rheumatic diseases as well as osteoporosis have been reported in women (Figure 2). Five patients had a previous diagnosis of malignancy at the time of diagnosis of PMR. In three of them, the malignancy occurred more than five years before the diagnosis of PMR. The most commonly diagnosed malignancies were breast cancer, which was diagnosed in three patients, malignant melanoma, which was diagnosed in one patient and smouldering multiple myeloma, which was also diagnosed in one patient. In two patients, the malignancy was diagnosed after the diagnosis of PMR, and these malignancies included cases of renal cell carcinoma and essential thrombocythemia.

All patients received oral glucocorticoid therapy at the time of data analysis. The initial daily dose of methylprednisolone was 12 to 16 mg. Synthetic antimalarials were used as treatment in 20.41% of cases, while methotrexate was used in 14.29% of cases, mostly in cases with concomitant inflammatory rheumatic diseases. Azathioprine was used for the treatment of concomitant GCA in one patient. In 47 (95.92%) patients, remission of PMR was achieved at the time of analysis, and the remaining two patients had recently been diagnosed with PMR. Relapse was reported in two (4.08%) cases.

DISCUSSION

The results of our study confirmed that PMR is more common in women, like most inflammatory rheumatic diseases, and the most common symptom was joint pain (10). Given that this is a condition that commonly affects the elderly population, a high incidence of arterial hypertension is expected (11, 12). It is known that long-term glucocorticoid therapy may lead to the occurrence of new or dysregulation of existing diabetes in these patients, and in the case of prolonged treatment there is an increased risk of osteopenia and / or osteoporosis progression. Also, long-term use of glucocorticoids promotes accelerated atherosclerosis, despite the known fact that adequate control of systemic inflammation in inflammatory rheumatic diseases has a protective effect on the vascular endothelium (13–17). The incidence of osteoporosis, heart disease, and type 2 diabetes, despite relatively long-term glucocorticoid therapy, has been reported in approximately one-third of our patients. Similar results were presented in the study conducted by Shbeeb et al. after analysing the connection between glucocorticoid therapy and the occurrence of these comorbidities in patients with PMR. According to this study, the incidence of diabetes, atherosclerosis, and osteoporosis is similar in patients with PMR who received glucocorticoid therapy and the control group (18). Based on these data, it can be concluded that relatively small doses of glucocorticoids used in the treatment of PMR suppress systemic inflammation with a relatively low incidence of adverse effects and have a protective effect on inflammation-mediated endothelial and bone damage (19, 20).

A group of Italian authors showed, on a relatively small number of subjects, that 12.5 mg of prednisolone per day is a sufficient dose for the start of PMR treatment (21). These data indicate a good efficacy of glucocorticoid therapy in the treatment of PMR, which has also been confirmed in the case of our patients. The duration of glucocorticoid therapy should be at least 1–3 years, and in patients with high CRP and / or ESR levels, long-term treatment with minimal doses of prednisolone is recommended to prevent relapse (22, 23).

One of the aims of our study was to determine how often PMR occurs with malignancies. In the group of our patients, we recorded only three cases of malignancies that occurred in the period of one year before or after the diagnosis of PMR. One patient was diagnosed with multiple myeloma one year before she was diagnosed with PMR, while two other patients were diagnosed with essential thrombocythemia or kidney cancer several months after being diagnosed with PMR. Therefore, in our group of patients, PMR proved to be a paraneoplastic syndrome in only three patients, while malignancies that were diagnosed several years before the diagnosis of PMR can hardly be considered in this context. Since the elderly population was analysed in this study, we expected a more frequent occurrence of malignancies (24, 25), which in the end was not recorded. Therefore, we cannot state with certainty that PMR can be viewed as part of the paraneoplastic syndrome, which has also been concluded in some of the recently published reviews (7, 26). The suspected paraneoplastic syndrome should be confirmed by the atypical clinical features of PMR, which include, for example, the absence of prolonged morning stiffness, therapeutic response to glucocorticoids, or the absence of radiologically confirmed bursitis of the shoulders and hips (26). However, in a 2018 review by Partington et al., the connection of PMR with the occurrence of malignancies, especially haematological ones, was not rejected. In summary, a connection with malignancies was confirmed in seven studies, while in nine of the analysed studies no connection between PMR and malignancies was found (27). Two of our patients with malignancies that were diagnosed in the same period as PMR presented with typical clinical features which, in addition to pain and stiffness in the shoulder and pelvic girdle, manifested by hand swelling and pain with typical prolonged morning stiffness with a good response to glucocorticoid therapy. Further population research is needed to define a clear connection between PMR and occult malignant neoplasms.

The main challenge in the diagnosis of PMR is the early recognition of GCA symptoms to prevent the occurrence of disease complications such as vision loss. In addition to that, patients with concomitant GCA require higher doses of glucocorticoids (23). Literature data show that the incidence of GCA in PMR patients is 10 – 16%, which is in accordance with our results (3, 28). When it comes to other cases of concomitant inflammatory rheumatic diseases, three cases of seronegative arthritis, one case of rheumatoid arthritis and one case of generalised osteoarthritis have been reported, which is also in line with the current knowledge of the incidence of these diseases in PMR patients (26).

The disadvantage of this study is the small number of patients included, due to the fact that we have analysed data from only one hospital centre and performed only descriptive statistical analysis. In addition to that, it is a retrospective study based on the review of medical records, with no control group.

In conclusion, PMR is an inflammatory rheumatic disease which affects the elderly and is more common in women. In our group of patients, no significantly higher connection of the disease with the occurrence of malignancies nor with other inflammatory rheumatic diseases was found. Prospective population research is needed to define a clear connection between PMR and malignant neoplasms.

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Figure 1. Main presenting symptoms of polymyalgia rheumatica (PMR)

Figure 2. Comorbidities in patients with polymyalgia rheumatica (PMR)