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Reumatologia/Rheumatology
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Review paper

If something looks like an apple, is it necessarily an apple? Some considerations about so-called “statin-induced polymyalgia rheumatica”

Ciro Manzo
1

1.
Internal and Geriatric Medicine Department, Rheumatologic Outpatient Clinic Hospital „Mariano Lauro”, Sant’Agnello, Italy
Reumatologia 2019; 57, 3: 163-166
Online publish date: 2019/06/28
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Introduction

Polymyalgia rheumatica (PMR) is a common inflammatory rheumatic disease affecting older persons [1, 2]. Bilateral pain, aching and stiffness in the shoulders and pelvic girdle, associated with morning stiffness lasting more than 45 minutes, are typical manifestations. In some patients, an inflammatory pain in the neck is also present [3–5].
To improve the criteria specificity for PMR, the 2012 provisional European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) classification criteria used, for the first time, findings of shoulder (sub-deltoid bursitis, biceps tenosynovitis and/or gleno-humeral synovitis) and hip (synovitis and/or trochanteric bursitis) ultrasound (US) along with clinical presentations [6]. It worth mentioning that these classification criteria have been designed to discriminate patients with PMR from other mimics of PMR, and are not meant for diagnostic purposes. They supply high sensitivity and specificity [7]. However, even if they still request elevation of the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) concentrations as mandatory to classify the patient as PMR, normal ESR and CRP should not be a reason for exclusion for PMR [8–10].
The etiopathogenesis of PMR is still unclear and debated [11–13].

Statin-induced myopathy

Statins or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are widely used drugs, able to lower serum cholesterol levels and to reduce the risk of cardiovascular events. Statin-associated muscle disease is by far the most studied and the most common reason for discontinuation of therapy [14]. Statin-induced muscle disease can be classified in two main syndromes:
statin-induced necrotising inflammatory myopathy (SINIM) [15],
statin-associated muscle symptoms (SAMS) [16, 17].
SINIM is a rare autoimmune disease related to the presence of anti-HMG CoA reductase antibodies associated with a restricted human leucocyte antigen (HLA) type (DRB1*11:01). It is very rare, and has a reported incidence of less than 2 per million per year. Patients affected by SINIM develop symmetrical proximal myopathy with grossly elevated creatine kinase (CK). Symptoms persist despite cessation of statin therapy. Muscle biopsy reveals muscle fibre necrosis with minimal endomysial inflammatory infiltrates. Diagnosis is confirmed by the presence of anti-HMG CoA antibodies and characteristic findings on muscle magnetic resonance imaging (MRI).
By contrast, in patients affected by SAMS, proximal myalgia with/without increased CK levels and not raised ESR and CRP concentrations are typically reported. A number of factors including genetic predispositions and drug interactions have been associated with an increased risk of SAMS. For example, interactions due to co-administration of drugs sharing the same cytochrome P450 metabolic pathway may account for up to 60% of SAMS. Drugs such as glucocorticoids, gemfibrozil, protease inhibitors, antipsychotics such as risperidone and immunosuppressives such as cyclosporine, and common food-associated factors such as orange or cranberry juice and excess alcohol consumption have all been implicated. Last but not least important, vitamin D and coenzyme Q10 (CoQ10)/ubiquinone deficiencies can also favour or exacerbate this myopathy [18, 19].
In view of the muscular side effects, some investigators discussed the possibility that PMR could be induced by statins.

Polymyalgia rheumatica and statins. What does the literature say about it?

Until 2012, the association between PMR and statin therapy was anecdotal [20–22]. In all reported patients, ESR and CRP concentrations were raised while CK was normal.
In 2012, de Jong et al. [23] published their analysis using a case/non-case approach in Vigibase (the database of the WHO Uppsala Monitoring Centre), and postulated that the use of statins may be associated with increased occurrence of PMR. However, as the authors themselves underlined, some forms of bias were present, including the lack of information on the therapy of PMR (which is why it was impossible to determine whether clinical improvement was related to statin discontinuation or to treatment with prednisone) and the scarcity of clinical data in the database (which is why the authors were not able to recognize possible diagnostic misclassification).
To our best knowledge, only one new case has been published after this study: in 2015, Onat et al. [24] reported a 53-year-old female suffering from pain in her bilateral shoulders, hips and neck associated with morning stiffness lasting one hour and with proximal weakness, which ensued one week after daily therapy with 40 mg atorvastatin. In this case report, the onset of PMR after statin therapy was just a coincidence.

Polymyalgia rheumatica or polymyalgia rheumatica-like illness?

Polymyalgia rheumatica can mimic several diseases and differential diagnosis is not always easy. Moreover, some patients with PMR-mimicking diseases can have a fast (but transitory) response to systemic glucocorticosteroids (GCs). On the other hand, up to 30% of patients with PMR can fail to have a good response to GCs at 4 weeks. Finally, some patients diagnosed first with PMR may be reclassified as having a different disease during follow-up [25].
Since Bird’s criteria published in 1979, a variety of criteria have been proposed with different sensitivity and specificity [26]. Shoulder and hip US examinations can make an important contribution as proposed by EULAR/ACR classification criteria, but their usefulness is counterbalanced by the absence of pathognomonic findings [27, 28]. As highlighted by the EULAR/ACR collaborative group, patients with PMR were more likely to have abnormal ultrasound findings in the shoulder (particularly subdeltoid bursitis and biceps tenosynovitis), and somewhat more likely to have abnormal findings in the hips (particularly trochanteric bursitis and synovitis) than comparison subjects as a group [6]. As in the case report published by Onat et al. [24], US can make a relevant contribution in distinguishing a true PMR from a PMR-like illness induced by statins.
Moreover, as already highlighted, normal ESR and CRP should not be a reason for exclusion for PMR [10], and this may introduce additional diagnostic difficulties in patients suffering from proximal myalgia without increased CK levels and without raised ESR and CRP concentrations, occurring during statin therapy. Nevertheless, also in this particular subset of PMR patients, shoulder and hip US examination can result in settling the issue.

What’s in a name? Is that which we call polymyalgia rheumatica the same for all physicians?

As highlighted by other investigators, the risk that PMR could be a magic cauldron in which to put every long-lasting pain localized to scapular and pelvic girdles, quickly responding to GCs, is always just round the corner [29].
When studies are performed using incomplete databases, this risk is very high. In this specific case, we know that the general practitioner (GP) is usually the first physician who examines the PMR patient [4, 30, 31], that many PMR patients are not referred to rheumatologists [32], that the level of the GP’s diagnostic accuracy is often low [33], and that PMR is not a straightforward disease [25].
In this way, what was presented as a strength in the study performed by de Jong et al. [23], that is the evaluation of reports made by physicians, became a potential further bias. This is by no means the first time that studies performed using uncontrolled and incomplete databases generated statistically intriguing findings, without clinical significance.

Conclusions

PMR and SAMS are two completely different pathological conditions.
PMR involves articular or juxta-articular synovial structures and no muscular involvement is primarily described. SAMS is a myopathy.
However, the possibility that SAMS may worsen the clinical manifestations of a PMR patient should be taken into account in clinical practice and discontinuation of a drug should be proposed when a deterioration or relapse is not otherwise justifiable.
The author declares no conflict of interest.

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Copyright: © 2019 Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.






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