Statement of principle findings
This review found some evidence of an association between PMR and vascular disease, and possibly cancer, particularly in the first 6 months following diagnosis. However, the evidence for this is not robust.
The concentration of the apparent association between PMR and cancer in the first 6 months following diagnosis suggests the possibility of an element of misdiagnosis. This could occur as some of the features of PMR (myalgia, fatigue, weight loss, raised inflammatory markers) are also non-specific early features of some cancers. Furthermore, as time passed, the rate of diagnosis of cancer was found to drop down to the background population rate.
Regarding specific types of cancer, some studies have proposed there could be associations between PMR and haematological cancers. This includes Hodgkin’s and non-Hodgkin’s lymphoma [
56], myeloma [
68] and other myeloid malignancies [
63,
66]. An increase in the risk of lymphoma has been observed with RA, which has been postulated to be due to higher accumulated inflammatory activity in RA [
73]; a similar mechanism may lie behind the apparent increase in patients with PMR.
The overall trend of results suggests that PMR may be associated with an increased risk of the development of vascular disease. Knowing that both PMR and RA are inflammatory conditions, there is biological plausibility that PMR and vascular disease could be associated. However, the two largest studies, both based on population data from the UK, reported conflicting results: Hancock et al. [
58] stated that PMR was significantly associated with vascular disease, while Pujades-Rodriguez et al. [
60] reported a reduction in the risk (incidence rate ratio 0.88 (95% CI 0.83–, 0.94)). However, in the latter study when only patients with PMR were included, there was a slight increase in the proportion of patients with the condition who went on to have a vascular event compared to controls (23.24% compared to 20.43%).
These two studies employed similar approaches selecting with PMR from linked UK databases. However, a number of differences existed between the studies, including the age of participants (> 50 years only for Hancock et al. [
58] and > 18 years for Pujades-Rodriguez et al. [
60]), average years of follow up (7.8 and 3.13 years respectively) as well as the total number of patients found with PMR (3249 compared to 11,320 patients). Potentially, the variation in risk of vascular events between these studies could be explained by the differences in follow up or the age distribution of the study population.
Another reason for inconsistent evidence of an increase in vascular risk for patients with PMR may be the modulating effect that GCs have upon levels on inflammation. If the risk of vascular disease correlates with the presence of inflammation in the body, GC therapy would reduce this, which may then also reduce vascular risk. The study by Kremers et al. [
42] appears to bear this out. In this study, the risk of vascular events was lower in patients with PMR who were treated with GCs compared to those who were not. Further to this, Hancock et al. [
58] reported that the excess vascular risk in PMR reduced over time; this could reflect declining levels of inflammation.
Overall, although some studies dissent from this view, it appears that a diagnosis of PMR increases an individual’s risk of vascular disease. However, further research in this area is needed to add clarity.
Conversely, it appears that a diagnosis with PMR is associated with a reduction in mortality. This was demonstrated in three out of the four studies that reported it as an independent outcome. A possible explanation for this could again be surveillance bias. Patients with chronic illness (and especially PMR where regular assessment, follow up and monitoring are advised) are more likely to be under active follow up for their condition and any developing morbidity, particularly if related to well-recognised adverse effects of treatment, is likely to be identified and managed earlier.
There is a small amount of evidence that patients with PMR may be more likely to develop hypothyroidism [
31] and Parkinson’s disease [
49]. PMR and hypothyroidism both preferentially affect females, and therefore a similar autoimmune pathway may be present in both conditions. However, as has been pointed out, PMR does not share all of the characteristics of traditional autoimmune conditions, for example it lacks specific autoantibodies [
74]. Furthermore, it seems that PMR is not associated as strongly with other autoimmune conditions as would be expected if it was a pure autoimmune disease. Parkinson’s disease is a condition which predominantly affects older people, as does PMR, and therefore this association may just be a result of clustering of diagnoses in an older population.
Strengths and weaknesses
The main strength of the study was its deliberately broad scope and aim to include any study in which the risk of any comorbidity either before or after diagnosis with PMR was to be reviewed. Following the initial broad search, articles from the ‘grey literature’ were excluded and only articles fully published in peer-reviewed journals were included.
The potential limitations in this study arose not due to the protocol but rather because the majority of studies were of relatively poor quality. These risks included selection bias, surveillance bias and a lack of adequate control groups.
Selection bias within the included studies is a possibility in this review, as the majority of studies drew PMR cases from secondary care, either from hospital discharge data or from rheumatology outpatient clinics. Current UK guidelines suggest only referring atypical cases, cases of diagnostic uncertainty or treatment predicaments [
5,
14], meaning that in the UK 71–84% of patients with PMR are treated in the community by primary care physicians [
71,
72]. Therefore, the patient population in these studies may not accurately reflect the majority of those who are diagnosed with PMR. This may have artificially inflated the apparent differences in development of comorbidities between patients with and without PMR.
Another limitation is the risk of surveillance bias as discussed earlier around the apparent reduction in mortality [
75]. Some case–control studies attempted to deal with this by excluding comorbid disease found in the year prior to diagnosis [
63,
64,
67,
68], while in two observational cohort studies [
58,
60], controls were selected that had contacted a primary care service in the year the index cases were diagnosed. Finally, many of these studies assessed multiple variables, often > 30 different autoimmune conditions, increasing the likelihood of a chance finding (type II error).
Furthermore, we also noted that the range of comorbidities reported in the literature was more limited than we expected; for example, there were no studies which explicitly examined the risks of important and common conditions such as diabetes mellitus and asthma or other chronic respiratory conditions.
A further potential bias is the effect of GC therapy and the impact of this on the risks of comorbidities. As GC is the only widely accepted treatment for PMR, we could not exclude studies where patients were treated with GC. To reduce the impact of potential bias from GC treatment, we excluded studies in which direct complications of GC therapy were assessed. However, as discussed previously in relation to vascular risk, GC therapy is inevitable in PMR and therefore we could not completely mitigate this effect.