Review

Musculoskeletal involvement is a common extraintestinal manifestation of inflammatory bowel disease (IBD), occurring in 6–46% of patients.^1–4 The most common presentations, including arthritis, myalgias, enthesitis, and both drug- and nondrug-related myopathies, have been well described in the literature. Mogul and coworkers⁵ describe a case of isolated gastrocnemius myositis, a rare and poorly characterized musculoskeletal manifestation of IBD.

To date, only 9 cases of IBD-associated gastrocnemius myositis have been reported in the literature. Gender distribution has been essentially equal (5M:4F), and patient ages have ranged from 19 to 50 years of age. The presenting symptom of this rare myositis is isolated calf pain, and, based upon the few reported cases, it does not appear that the muscle symptoms mirror clinical bowel disease activity. However, it is possible that some patients have had smoldering mucosal disease and that the eventual resolution of their myalgia was due to the induction of remission of their luminal Crohn's activity with immunosuppressant medications. In the absence of larger case series describing the endoscopic evaluation of mucosal disease activity, inferences on the association with disease activity rely upon the information available in case reports.

The clinical presentation of musculoskeletal symptoms in IBD is protean, and an accurate diagnosis is often challenging. Symptoms can include localized joint pain, swelling, and warmth, as seen in pauci- or polyarticular arthropathies. Patients often present with characteristic back pain and stiffness, due to the axial skeleton involvement of spondyloarthropathies. Muscle stiffness, fibromyalgia-like symptoms, and localized muscle symptoms can all be manifestations of either a localized or generalized myopathy. Complicating the evaluation is the fact that musculoskeletal symptoms can be a result of IBD therapy, including agents such as corticosteroids, 5-ami-nosalicylates, and azathioprine/6-mercaptopurine. When evaluating an IBD patient with myalgia, it is important to obtain a detailed medication history, specifically focusing on the temporal association between medication initiation and symptom onset. However, the limitations of this approach should be kept in mind, as localized gastrocnemius myositis has been reported to precede the clinical diagnosis of IBD.⁶

The differential diagnosis of IBD-associated myositis can be broadly divided into localized and nonlocalized entities. The main nonlocalized myositides include dermatomyositis, polymyositis, and medication-associated myositis.^7–9 Localized muscle involvement has been described in extraocular muscles, as well as proximal muscles, both related and unrelated to steroid treatment. In cases involving the extraocular muscles, clinical presentation mimics thyroid ophthalmopathy, and thyroid function testing should be pursued during evaluation.^10,11 Other considerations in the differential diagnosis of localized myalgia in IBD include trauma, cellulitis, and venous thromboembolic disease.

Despite the rarity of IBD-associated myositis, there have been pathophysiologic mechanisms postulated in the literature. There may be a shared underlying immune-mediated phenomenon responsible for both the bowel and muscle inflammation, as described in a case by Shimoyama and colleagues.¹² The authors described a case of a proximal myopathy associated with Crohn's disease, with a deltoid muscle biopsy showing myositic changes, including inflammatory infiltrates in the perimysium, endomysium, and perivascular locations. In addition, biopsies exhibited staining for CD68-positive macro-phages and CD4- and CD8-positive T lymphocytes. The patient continued to have active and difficult-to-control bowel disease, resulting in colectomy. Pathologic examination of the colectomy specimen demonstrated CD68-positive macrophages, which, though nonspecific, may suggest a common immunologic pathogenesis. Heuss and associates¹³ reported a case of steroid-responsive gastrocnemius myositis associated with Crohn's disease and postulated a T-cell–mediated inflammatory process. In this case, muscle biopsy demonstrated focal necrotic changes, together with peri- and endomysial inflammatory infiltrates predominantly consisting of CD67- and CD68-positive cells, accompanied by CD8- and CD4-positive cells. It is also worth noting that there was severe inflammatory infiltration of connective tissue septa with granulocytes, as well as CD8-positive cells, in areas of otherwise normal muscle.

Laboratory evaluation in cases of gastrocnemius myositis is not particularly revealing, and the published cases have almost always reported normal results. Commonly ordered tests have included a complete blood count, muscle enzymes (creatine kinase, aldolase), sedimentation rate, antineutrophil cytoplasmic antibody, liver function tests, and antinuclear antibody. These tests are most helpful for excluding alternate etiologies of muscle pain, and not for confirming the presence of myositis. In previously reported cases of myositis associated with features suggestive of polymyositis and dermatomyositis, aldolase and creatine kinase levels were increased.⁸ Imaging is more useful for providing information regarding the underlying disease process. An initial venous Doppler ultrasound is indicated, depending upon the clinical presentation, to exclude thromboembolic disease, a common complication in IBD patients. Earlier case reports of gastrocnemius myositis have used magnetic resonance imaging, which demonstrates diffuse inflammation of the involved muscle groups with contrast enhancement. The gold standard for diagnosis is muscle biopsy, though histologic findings have varied among the reported cases.

Histologic findings in the reported cases of gastrocnemius myositis span the spectrum of granulomatous myositis, nonspecific myositis, and vasculitis.^6,14 The vasculitis described on histologic examination can be either necrotizing, resembling changes seen in polyarteritis nodosa, or nonnecrotizing. Typically, these cases have not had concomitant evidence of systemic myositis or vasculitis.^14–16 The various histologic findings on muscle biopsies in this condition make interpretation of the disease entity difficult. Are we dealing with the same disease, or is this a heterogeneous condition with multiple subsets? In the reported cases, response to steroids has not been related to the varied histologic subsets, though it is too early to draw any inferences from the limited data on this entity.

The majority of previously reported cases of gastrocnemius myopathy associated with Crohn's disease have responded to steroids,⁵ though at doses much higher than those used to treat luminal IBD (up to 60–80 mg daily). However, 3 of the 9 cases have required the addition of an immunomodulator in order to completely control muscle symptoms. Two cases reported by Disdier and coworkers¹⁴ required the addition of cyclophosphamide and azathioprine to systemic corticosteroids. Additionally, the case reported by Diószeghy and colleagues¹⁷did not respond to either steroids or nonsteroidal anti-inflammatory drugs. With a longer follow-up, it is possible that some of the other case reports would have required immunomodulators for maintenance of remission, as with the case described by Mogul and associates. As mentioned above, histologic findings do not appear to be related to treatment response or to the need for the addition of an immunomodulator. Although the cases reported by Disdier and coworkers showed vasculitis on biopsy and required additional immunomodulator treatment, another case by Gilliam and associates¹⁸ had similar findings on pathology, but the patient responded to prednisolone monotherapy. The addition of more aggressive treatment, in our view, should be limited to patients who have confirmatory muscle biopsies and who are either steroid-refractory or, as in this case, exhibit symptom recurrence following the cessation of steroids. Additionally, treatment escalation should be considered if there is evidence of active intestinal inflammation, as the link between myositis and active intestinal inflammation remains unclear.

The current reported data on gastrocnemius myositis, an uncommon extraintestinal manifestation of IBD, is limited to case reports. As such, there are no good evidence-based guidelines on the standard evaluation and treatment of this rare condition. It is reasonable to proceed on a case-by-case basis, beginning with a noninvasive work-up, realizing that laboratory testing is often unrevealing, and excluding the differential diagnoses of localized and systemic myositis detailed above. Imaging, particularly magnetic resonance imaging, may be helpful for demonstrating inflammation surrounding the involved muscles. The gold diagnostic standard, muscle biopsy, should be performed to confirm the diagnosis, though histologic findings in IBD-associated myositis can be varied. Treatment escalation to immunomodulator medications or biologic treatments should be limited to patients who have confirmatory pathology, unless there is concern for active bowel inflammation that warrants more aggressive therapy. Based upon the available reports, approximately one third of patients require additional immunosuppressive therapy beyond corticosteroids.

The rarity of gastrocnemius and other forms of IBD-associated myositis make them difficult to study on a large scale. Additional case reports in the literature may provide a better understanding of the diagnosis and treatment of this disease and will hopefully raise the awareness of clinicians to consider this rare extraintestinal manifestation of IBD. Through continued awareness and reporting of this diagnosis, hopefully, we will be able to formulate more specific and useful guidelines regarding clinical and pathologic evaluation, which will lead to greater insight into more effective therapies and therapeutic strategies.