Sarcoidosis is a multisystem granulomatous disorder that may involve many organs. Beside organ specific symptoms, non-specific constitutional complaints such as fatigue and general weakness are frequent. The granuloma formation in sarcoidosis is driven by an array of cytokines such as tumour necrosis factor (TNF)-α, interleukin (IL)-6, interferon (INF)-γ and others. High circulating levels of such cytokines have been found in sarcoidosis and may be responsible for provoking the constitutional symptoms fatigue and general weakness.^1–4

Fatigue and general weakness may be the reason why patients with sarcoidosis frequently experience exercise intolerance.^5,6 In one study 67% of patients with sarcoidosis terminated their peak exercise test due to “leg complaints”.⁷ Skeletal muscle weakness may therefore be responsible for the limited exercise capacity, although quadriceps muscle force and handgrip force were found to be normal in the first study to investigate skeletal muscle force in patients with sarcoidosis,⁸ but most of these patients did not complain of fatigue.

In this issue of Thorax Spruit et al⁹ report that skeletal muscle weakness is present in patients with sarcoidosis who complain of fatigue, and that the presence of skeletal muscle weakness is associated with reduced health status as assessed by two questionnaires and also with reduced exercise capacity. In addition, quadriceps muscle force was inversely related to fatigue but not to the circulating levels of several proinflammatory cytokines. This would indicate that skeletal muscle weakness rather than the circulating cytokines are responsible for the complaints of fatigue in these patients. Interestingly, quadriceps muscle force was inversely related to the daily dose of corticosteroids in patients who received such treatment. This would imply that steroid induced myopathy may be one factor for reduced skeletal muscle function in sarcoidosis, although no differences in muscle strength were found in this study between patients who were taking steroids and those who were not.

Other factors may therefore be involved in the development of skeletal muscle weakness. One could be reduced physical activity which can induce general deconditioning in these patients who complain of fatigue, general malaise and depression, all of which will probably reduce the patients’ physical activities. One major shortcoming of the paper by Spruit et al is that they did not investigate patients who did not complain of fatigue so it is difficult to generalise their findings to other patients with sarcoidosis. Would reduced skeletal muscle strength also be present in sarcoidosis patients without fatigue? We do not know since the number of patients studied in the first paper on skeletal muscle strength⁸ was probably too small to exclude a type II error.

Another factor contributing to the muscle weakness could be involvement of the skeletal muscle by sarcoidosis.¹⁰ The first published case of sarcoidosis of the skeletal muscles was reported as early as 1908 by Licharew who presented a girl with many palpable nodules in the muscle.¹¹ In 1952 it was recognised that inactive sarcoidosis granulomas might frequently be found in clinically normal muscles.¹² In 50–75% of patients with sarcoidosis a muscle biopsy may detect non-caseating granulomas.^12,13 None of the patients in these screening studies had symptoms suggesting muscle involvement. This symptomless involvement resolves in the majority of cases during the natural course of the disease.

Clinically symptomatic skeletal muscle involvement in sarcoidosis is rare. There are two manifestations—acute polymyositis and chronic myopathy. Acute polymyositis has been reported in no more than 15 cases.¹⁰ The proximal shoulder and pelvic girdle muscles are most often involved and the condition is often associated with fever, erythema nodosum, myalgia, and polyarthralgia. The levels of muscle enzymes such as creatine phosphokinase may be raised. Chronic myopathy is also rare. In a review of 800 patients with confirmed sarcoidosis Silverstein and Siltzbach¹⁴ found that only two had severe persistent sarcoid myopathy and, in the recent prospective ACCESS study, only one of 215 patients had initial muscle involvement.¹⁵ The symptoms are bilateral weakness and wasting of proximal muscles. Whereas corticosteroids are clearly indicated in these forms of clinically apparent muscle involvement, diagnostic difficulty may arise when myopathy occurs in patients with sarcoidosis under treatment with corticosteroids since corticosteroid myopathy has a similar distribution to that seen in sarcoid myopathy.

What are the practical issues emerging from the paper by Spruit et al? For differential diagnostic purposes, the muscle force tests are not useful since they do not discriminate between the possible different causes of skeletal muscle weakness in sarcoidosis. As previously mentioned, the causes may be limited physical activities, sarcoidosis involvement of the muscles, or corticosteroid myopathy. Ideally, we should have discriminating tests available which would be non-invasive and not depend on muscle biopsy. Less invasive techniques such as electromyography and nerval conductance velocity may differentiate between myopathy (either sarcoidosis or corticosteroid induced) and weakness due to limited exercise. Unfortunately, such neurological measurements for determining the cause of the skeletal muscle weakness were not included in the present study.

If we apply muscle force tests more frequently in patients with sarcoidosis and find reduced muscle strength, how should we manage such patients? We would expect that most of these patients also have the subjective complaint of fatigue, so the more general question would be how to manage skeletal muscle weakness and fatigue in sarcoidosis. Given the very rare clinically apparent skeletal muscle involvement by sarcoidosis granuloma and the very frequent subclinical muscle involvement which most probably represents harmless granuloma formation without impairment or wasting of the skeletal muscle, one would not start prednisone treatment for these patients but, rather, would recommend that they undergo controlled physical training programmes. As Spruit et al discuss, the positive effect of exercise training in chronic pulmonary and cardiac disease has been shown for other conditions and may reduce clinical symptoms of fatigue, anxiety, and depression.

In this regard the great merit of the paper by Spruit et al is to remind the readers of Thorax that sarcoidosis is a complex multiorgan disease with multiple non-specific symptoms which go beyond the usual experience of chest physicians. The study underlines the importance of taking such patient complaints seriously, performing adequate investigations which may include muscle force tests, and giving them the appropriate treatment which would probably include an exercise programme to improve their physical activity which would also reduce the complaint of fatigue.