Discussion

IBM was originally identified as a ‘steroid resistant’ form of PM but on further assessment was noted to have specific histopathological and clinical features.17 ,18 This led to the development of the histopathologically focused Griggs diagnostic criteria. Individually, the histopathological features of the Griggs criteria are non-specific.19–22 However, when present together they are considered diagnostic of IBM. Clinical experience over the intervening 40 years has supported early observations that IBM is associated with a very characteristic pattern of muscle involvement with predilection for the long finger flexors and quadriceps, and occasionally the muscles associated with swallowing.1 ,23 In our experience, patients with this clinical presentation, who do not fulfil the Griggs histopathological criteria, are at least as common as those who do. Other studies have described clinical or histopathological findings in patients not fulfilling Griggs criteria but detailed clinical data are lacking in most and long term outcome data on clinically diagnosed patients are lacking.1–3 ,8 ,13–16 Two of these studies included clinical examination findings in agreement with our current findings.1 ,13

We have characterised the clinical and histopathological features of patients with IBM and found that the clinical features are more sensitive than the histopathological findings in establishing a diagnosis.

The demographics, clinical features, speed of disease progression and response to immunosuppressive therapy in our cohort were similar to previous studies.1 ,9 ,13 ,24 Although dysphagia affects a substantial proportion of patients with IBM at some stage during the disease course,25 we found it to be uncommon as an initial symptom, although a proportion had developed mild dysphagia by the time patients were seen within our specialist service. We found no differences in clinical characteristics or disease progression between clinically and histopathologically diagnosed patients. In addition, cases with and without rimmed vacuoles, sometimes considered a sine qua non for diagnosis, were clinically identical except for age at biopsy; specifically, there was no difference in the pattern of weakness or disease progression. These findings confirm our long term observation that we are dealing with a clinically homogenous disorder, irrespective of whether patients are diagnosed on the basis of clinical or histopathological criteria and that IBM can be accurately and reliably diagnosed without fulfilling all of the Griggs histopathological features. In concordance with previous studies, we found that age at symptom onset predicted disease progression.24 ,26 Older onset patients had a more rapid decline and required walking aids earlier. Suggested reasons for this have included age related sarcopenia and the higher frequency of comorbidities in older patients.2 ,24 Although our data appeared to show that male patients reached disability endpoints more rapidly than female patients, this was an effect of age.

The absence of the Griggs histopathological features in a substantial proportion of our cohort may be due to the vagaries of sampling, or alternatively these features may indicate an advanced stage of disease progression and are therefore absent on the initial assessment.1 ,3 Because of the insidious nature of IBM, it is difficult to accurately identify disease onset or duration prior to diagnosis; however, we found that patients without rimmed vacuoles on muscle biopsy were younger at the time of biopsy than patients with them. This observation lends support to the notion that some of the histopathological features are absent early in the disease course and, therefore, are of limited diagnostic potential at the time of initial presentation. Differences in the frequency of partial invasion and mitochondrial changes have previously been described between cases with and without rimmed vacuoles.13 ,15 In agreement with a previous publication,13 we found the absence of both partial invasion and mitochondrial abnormalities to be strong evidence against the diagnosis of IBM. Divergent observations to ours may be due to differences in staining techniques and methods of assessment; unlike other studies we did not quantify the number of affected fibres. It has been suggested that a further biopsy be considered to confirm the diagnosis if the Griggs criteria are not satisfied at first sight.5 ,11 We found that this is unlikely to achieve a diagnosis in the majority of these patients and is unnecessary when the characteristic pattern of weakness is present and the histopathological findings supportive of, and not inconsistent with, the diagnosis of IBM.

The Griggs criteria were widely considered to be the gold standard diagnostic tool for IBM. They have been instrumental in helping to identify the clinical characteristics particular to IBM. However, they lack sensitivity; 73% of our patients failed to fulfil them on initial assessment. Subsequently, the 1997 ENMC criteria were published.6 These place less emphasis on the histopathological features and therefore are more sensitive.27 Although these criteria were an improvement on the Griggs criteria they do not incorporate the characteristic lower limb pattern of weakness, which we found to be more common than finger flexor weakness at presentation, and they still require the presence of some of Griggs’ histopathological features. The advantage of the 2011 ENMC criteria is that they are more sensitive than the Griggs criteria and the 1997 ENMC criteria; the addition of the lower limb pattern of weakness, limits on age and CK makes them more specific. Therefore, the diagnosis of IBM can be made securely, even in the absence of Griggs’ histopathological features. Although the majority of patients fulfilling the Griggs criteria also have the diagnostic pattern of weakness associated with IBM, inevitably some patients with IBM will not satisfy the clinical criteria. A further strength of the 2011 ENMC criteria is that a diagnosis of clinicopathologically defined IBM can be made when the diagnostic pathological features are present in combination with supportive clinical features. This complementary approach means that the 2011 ENMC criteria are the most specific and sensitive criteria to date. However, some may feel that predominantly clinical criteria lack specificity and may lead to the inclusion of patients without IBM in studies. In our experience, the characteristic pattern of weakness associated with IBM is not seen in conditions important in the differential diagnosis of IBM. To confirm this, we reviewed the clinical examination findings, at presentation and with follow-up, in myopathies considered important in the histopathological differential diagnosis of IBM, including 15 cases of steroid responsive myositis, two cases of hereditary inclusion body myopathy and 10 cases of myofibrillar myopathy. None of these patients exhibited the characteristic pattern included in the 2011 ENMC criteria, suggesting that these clinical criteria do have sufficient specificity to differentiate IBM from its mimics.

We acknowledge the limitations to our study. It could be argued that to confirm the sensitivity of the clinical criteria a further biopsy should have been performed in those patients that did not fulfil the pathological criteria at presentation. However, we have shown that clinically diagnosed patients are indistinguishable from those with Griggs histopathological features and therefore repeating the muscle biopsy is unnecessary. Currently, in the absence of a ‘gold standard’ diagnostic test for IBM, we feel that clinical assessment with a supportive biopsy should be considered the ‘gold standard’ rather than the histopathological findings present in a small biopsy sample. Patients in our region with neuromuscular disease are referred early to specialist neuromuscular services which are not universally available. The majority of patients were assessed and managed by a single individual, possibly affecting the speed of diagnosis and management. Having a single assessor also had the advantage of uniformity of the clinical assessment and data collection. The study was retrospective which could introduce patient recall bias, particularly with regard to timings in this slowly progressive disease. Because many patients were followed-up, a complete dataset was collected for nearly every patient. In addition, we included all patients with a final diagnosis of IBM, not only those presenting with typical IBM. As the majority of our patients did not receive immunosuppressive therapy the results from our study are an accurate representation of the natural history of IBM.

Diagnostic criteria are useful in defining homogeneous cohorts for research purposes but are often impractical for everyday clinical use. We have shown that the characteristic pattern of weakness associated with IBM is found in the majority of patients at presentation and that this is independent of the histopathological features, supporting the diagnostic utility of the clinical examination and the addition of a clinically defined category to the diagnostic criteria. In addition, continued adherence to histopathologically predominant criteria will lead to misdiagnosis and inappropriate treatment of many patients with IBM and exclude a substantial proportion of patients from research studies, potentially leading to erroneous conclusions being drawn about the pathogenesis and treatment outcomes in IBM. Our data reveal that the clinical examination is highly sensitive and specific for IBM and that the majority of patients will not show all of the histopathological features previously considered to be diagnostic of IBM. However, we believe that the clinical and pathological assessments are complementary to one another and we continue to include muscle biopsy as part of the diagnostic assessment. The majority of patients will show some features consistent with the diagnosis on muscle biopsy and these are included in the proposed clinical diagnostic criteria. Whether the inclusion of newer immunohistochemical techniques such as p62 staining will lead to a further improvement in the histopathological diagnosis is currently uncertain. Very rarely, biopsy may reveal an unexpected alternative diagnosis. We are aware of patients who have been suspected by non-muscle specialists as having IBM but biopsy has led to alternative diagnoses, including myofibrillar myopathy, with a specific mutation identified, or granulomatous myopathy (sarcoid). This supports the continued inclusion of muscle biopsy in the diagnostic workup, especially if there is any clinical uncertainty.