Case Challenges

An Interesting Case of Inclusion Body Myositis after 48-Week Treatment Course

A 64-year-old male presents to the gastroenterology/hepatology clinic with chief complaints that included increased shortness of breath since stopping his interferon therapy, progressive lower-extremity weakness and dysphagia.

The shortness of breath was exertional, but not obvious with rest or at night. He denied having air hunger and was without chest pain. During this period, the patient began to notice dysphagia and had complaints of pills getting stuck mid-esophagus. His lower-extremity weakness began during the last couple of months of interferon therapy, but significantly worsened after the medications were discontinued. Initially, he reported the sensations of tingling on his feet and lower legs that progressed to a sensation of heaviness. His lower-extremity weakness was symmetrical and had progressed to the point where he needed to use his hands to lift his legs up onto the exam table. He complained that the muscles in his legs were aching, but denied having acute pain or redness in the calves. For the past 2 weeks before presentation, the sensation of heaviness moved to his upper extremities as well. The patient noticed that his gait was unsteady and felt that he tended to drift to the side while ambulating. His weight had increased during the past 6 weeks, but he felt it was secondary to increased intake after cessation of therapy rather than fluid accumulation in his extremities. He was without nausea, indigestion, abdominal pain or any adverse issues with his bowels. He denied any issues with short-term memory loss or confusion.

Andrea Scherschel

Course of Interferon Therapy

At the time he began his therapy for hepatitis C virus genotype 1, the standard of care was boceprevir (Victrelis, Merck), pegylated interferon and ribavirin. This was the patient’s third attempt at treatment for his HCV. His initial therapy occurred in the late 1990s with interferon alfa and ribavirin, and then a second attempt in 2005 with pegylated interferon and ribavirin. His viral load became undetectable during the second course of therapy, but he unfortunately experienced viral relapse. He did not report any lower-extremity muscle weakness with his prior interferon therapies. Further pertinent history includes prostate cancer resolved with radiation, erectile dysfunction and a cholecystectomy.

Upon initial presentation to Scripps Clinic in 2012, he was noted to have stage I fibrosis from his previous liver biopsy in 2005. FIBROSpect II testing from August 2012 was notable for a score of 14, which is consistent with the findings from his previous liver biopsy. His baseline lab values were notable for hemoglobin of 14.7 g/dL, a platelet count of 159, albumin of 3.9 g/dL, total bilirubin of 0.9 mg/dL, an alanine aminotransferase (ALT) of 54 IU/L and an aspartate aminotransferase (AST) of 43 IU/L. His viral load was high at 12.9 million IU/mL. His IL28B genotype was CT and he was negative for coexisting liver disease. The most recent therapy described above commenced on Nov. 30, 2012, with just pegylated interferon and ribavirin. The boceprevir was added 4 weeks after the start of therapy. By week 6, his viral load had decreased to 230 IU/mL and was completely undetectable by week 12, as it remained through treatment.

The patient began to get anemic at week 6 of therapy, shortly after the addition of boceprevir to the regimen. His hemoglobin nadir occurred at week 12: 9.4 g/dL. The ribavirin was lowered to 800 mg per day, but after 2 weeks did not improve. His anemia was symptomatic with fatigue and shortness of breath with exertion. At that point, the ribavirin was reduced to 600 mg per day and he received an injection of epoetin alfa (Procrit, Janssen). Following this, he received epoetin alfa intermittently until his anemia significantly approved at week 35. The ribavirin dose was left at 800 mg per day and the patient received full-dose interferon throughout his entire treatment. His ALT/AST remained low throughout therapy until week 44 when his ALT increased slightly from 33 IU/L to 59 IU/L. At the corresponding visit, the patient had complaints of weakness in his lower extremities, but was without shortness of breath or dysphagia. When evaluated 6 weeks later, his symptoms had markedly increased and his ALT/AST rose to 139 IU/L and 154 IU/L, respectively.William B. Minteer

William B. Minteer

Initial Management

Stat labs were drawn at the time of the appointment. He was not anemic (H/H 14.8/45.5) and the platelet count was stable at 158. Electrolytes and kidney function were normal. His ALT/AST had increased to 201 IU/L and 192 IU/L, respectively. Parameters of synthetic liver function were normal. His lactate dehydrogenase (LDH) was elevated at 992 IU/L and creatine kinase was markedly elevated at 4,215 U/L. His HCV RNA by polymerase chain reaction was not detected.

While we were waiting for the lab results, he underwent bilateral lower-extremity venous Doppler to assess for a possible deep vein thrombosis (DVT). The Doppler study was negative. A chest X-ray was unremarkable. His O 2 saturation was 98%. Vital signs were stable. A brief initial neurologic exam was notable for decreased patellar reflexes, and marked loss of strength in both the upper and lower extremities. His gait was unsteady. After the receipt of his creatine kinase level, he was admitted to the hospital for further evaluation and testing.

Differential Diagnosis

Initially, when the patient came to clinic we were worried about his shortness of breath and weakness. Top on the list of differential diagnoses were heart failure, pulmonary embolism and, possibly, bleeding. He was sent for a chest X-ray while we waited for labs to arrive. The complete blood count came back normal, followed shortly by the report of a normal chest X-ray and negative Doppler report. Additional concerns were related to the ascending weakness and possible Guillain-Barré syndrome. While arranging the echocardiogram, the patient’s creatine kinase value was received and he was admitted to the hospital for further evaluation of myositis.

Catherine T.
Frenette

Upon admission, further studies were done, including blood work for syphilis, HIV, autoimmune hepatitis, rheumatoid arthritis, a Quantiferon and a myositis panel — all of which were negative. A lumbar puncture was performed to rule out Guillain-Barré syndrome with negative cerebrospinal fluid analysis. A CT scan of the chest/abdomen/pelvis and an MRI of the lower extremities were negative for any acute abnormality. The echocardiogram did not show evidence of any valvular disease, pulmonary hypertension or congestive heart failure. The ejection fraction was 65.7%. The esophogram did not reveal stricture, mass, obstruction, hiatal hernia or reflux. The electromyogram was positive for inflammatory myopathy, electromyographically of moderate severity. A muscle biopsy was performed that was notable for inflammatory myopathy, active and chronic, with features consistent with inclusion body myositis. The patient was started on high-dose IV methylprednisolone sodium succinate and noticed an almost immediate improvement in his symptomatology.

Discussion

Interferon is a well-known immune system up-regulator that can exacerbate any autoimmune disorder. There are many case studies in the literature demonstrating that interferon can cause myositis, which can be simply defined as an inflammatory infiltrate of the skeletal muscle.

Inclusion body myositis is part of a group of inflammatory myopathies that result in proximal muscle weakness, muscle enzyme elevations (creatine kinase, LDH), and extramuscular manifestations such as fever, rash and weight loss. Myositis-specific antibodies are present in the serum in about 50% to 60% of the cases, and they are directed against proteins in the nucleus and cytoplasm. Sporadic inclusion body myositis is distinctive in that it involves symmetric or asymmetric involvement of proximal or distal muscles occurring after age 50 years in a male-to-female ratio of 3:1. Inclusion body myositis can have severe systemic effects. For example, when inclusion body myositis affects the gastrointestinal tract, dysphagia with solids and liquids may be a predominant feature. The pharynx and upper esophageal sphincter are composed of skeletal muscle and, thus, aspiration/aspiration pneumonia may be a possible complication of the disease. Both esophageal and gastric emptying may be delayed.

Patients will exhibit marked increases in both creatine kinase and LDH, which is consistent with muscle injury. Both ALT and AST levels will be high. The erythrocyte sedimentation rate and C-reactive protein may be increased. The mainstay of treatment includes corticosteroids.

Conclusion

When myositis occurs from interferon, the prognosis is good with resolution of the symptoms quickly noticeable after withdrawal of the interferon and with addition of corticosteroids. The prognosis is less favorable when the myositis is from other etiologies, especially inclusion body myositis. Our patient responded rapidly to prednisone, noting an almost immediate improvement in his symptoms. And, on a positive note, his HCV RNA remains undetectable, representing a virologic cure.

References:
Aisa Y. Intern Med. 2001;40:1109-1112.
Alric L. Rev Med Interne. 2000;21:542-546.
Anderlini P. Cancer. 1995;76:678-679.
Aouba A. Joint Bone Spine. 2011;78:94-97.
Arai H. Lancet. 1995;345:582.
Blasini AM. J Clin Rheumatol. 1996;2:236-237.
Colomba C. J Antimicrob Chemother. 2012;67:249-250.
Ebert EC. Aliment Pharmacol Ther. 2010;31:359-365.
Gabrielli M. Am J Gastroenterol. 2003;98:940.
Greenfield SM. BMJ. 1994;309:512.
Hauschild A. Br J Dermatol. 2001;144:215-216.
Horsmans Y. Lancet 1995;345:1236.
John A. Indian J Gastroenterol. 2007;26:147-148.
Matsuya M. Intern Med. 1994;33:806-808.
Meyer O. Joint Bone Spine. 2009;76:464-473.
Ozdag F. J Dermatolog Treat. 2001;12:167-169.
Ramos-Casals M. Rheumatology. 2003;42:818-828.
Reinhold U. Lancet. 1997;349:540-541.
Ueno Y. J Clin Rheumatol. 1996;2:236-237.
van Londen GJ. J Clin Oncol. 2001;19:3794.
Venezia G. Dig Liver Dis. 2005;37:882-885.
Warabi Y. Rinsho Shinkeigaku. 2004;44:609-614.
Weidensaul D. Arthritis Rheum. 1995;38:437-439.
For more information:
Andrea Scherschel, MSN, FNP, and William B. Minteer, BS, are from the department of gastroenterology and hepatology at Scripps Clinic in La Jolla, Calif. Catherine T. Frenette, MD, is from the department of organ transplant at Scripps Clinic and is a member of the HCV Next Editorial Board. Frenette can be reached at Scripps Green Hospital Center for Organ and Cell Transplantation, 10666 N. Torrey Pines Road N200, La Jolla, CA 92037; email: frenette.catherine@scrippshealth.org.
Disclosure: The authors report no relevant financial disclosures.

A 64-year-old male presents to the gastroenterology/hepatology clinic with chief complaints that included increased shortness of breath since stopping his interferon therapy, progressive lower-extremity weakness and dysphagia.

The shortness of breath was exertional, but not obvious with rest or at night. He denied having air hunger and was without chest pain. During this period, the patient began to notice dysphagia and had complaints of pills getting stuck mid-esophagus. His lower-extremity weakness began during the last couple of months of interferon therapy, but significantly worsened after the medications were discontinued. Initially, he reported the sensations of tingling on his feet and lower legs that progressed to a sensation of heaviness. His lower-extremity weakness was symmetrical and had progressed to the point where he needed to use his hands to lift his legs up onto the exam table. He complained that the muscles in his legs were aching, but denied having acute pain or redness in the calves. For the past 2 weeks before presentation, the sensation of heaviness moved to his upper extremities as well. The patient noticed that his gait was unsteady and felt that he tended to drift to the side while ambulating. His weight had increased during the past 6 weeks, but he felt it was secondary to increased intake after cessation of therapy rather than fluid accumulation in his extremities. He was without nausea, indigestion, abdominal pain or any adverse issues with his bowels. He denied any issues with short-term memory loss or confusion.

Andrea Scherschel

Course of Interferon Therapy

At the time he began his therapy for hepatitis C virus genotype 1, the standard of care was boceprevir (Victrelis, Merck), pegylated interferon and ribavirin. This was the patient’s third attempt at treatment for his HCV. His initial therapy occurred in the late 1990s with interferon alfa and ribavirin, and then a second attempt in 2005 with pegylated interferon and ribavirin. His viral load became undetectable during the second course of therapy, but he unfortunately experienced viral relapse. He did not report any lower-extremity muscle weakness with his prior interferon therapies. Further pertinent history includes prostate cancer resolved with radiation, erectile dysfunction and a cholecystectomy.

Upon initial presentation to Scripps Clinic in 2012, he was noted to have stage I fibrosis from his previous liver biopsy in 2005. FIBROSpect II testing from August 2012 was notable for a score of 14, which is consistent with the findings from his previous liver biopsy. His baseline lab values were notable for hemoglobin of 14.7 g/dL, a platelet count of 159, albumin of 3.9 g/dL, total bilirubin of 0.9 mg/dL, an alanine aminotransferase (ALT) of 54 IU/L and an aspartate aminotransferase (AST) of 43 IU/L. His viral load was high at 12.9 million IU/mL. His IL28B genotype was CT and he was negative for coexisting liver disease. The most recent therapy described above commenced on Nov. 30, 2012, with just pegylated interferon and ribavirin. The boceprevir was added 4 weeks after the start of therapy. By week 6, his viral load had decreased to 230 IU/mL and was completely undetectable by week 12, as it remained through treatment.

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The patient began to get anemic at week 6 of therapy, shortly after the addition of boceprevir to the regimen. His hemoglobin nadir occurred at week 12: 9.4 g/dL. The ribavirin was lowered to 800 mg per day, but after 2 weeks did not improve. His anemia was symptomatic with fatigue and shortness of breath with exertion. At that point, the ribavirin was reduced to 600 mg per day and he received an injection of epoetin alfa (Procrit, Janssen). Following this, he received epoetin alfa intermittently until his anemia significantly approved at week 35. The ribavirin dose was left at 800 mg per day and the patient received full-dose interferon throughout his entire treatment. His ALT/AST remained low throughout therapy until week 44 when his ALT increased slightly from 33 IU/L to 59 IU/L. At the corresponding visit, the patient had complaints of weakness in his lower extremities, but was without shortness of breath or dysphagia. When evaluated 6 weeks later, his symptoms had markedly increased and his ALT/AST rose to 139 IU/L and 154 IU/L, respectively.William B. Minteer

William B. Minteer

Initial Management

Stat labs were drawn at the time of the appointment. He was not anemic (H/H 14.8/45.5) and the platelet count was stable at 158. Electrolytes and kidney function were normal. His ALT/AST had increased to 201 IU/L and 192 IU/L, respectively. Parameters of synthetic liver function were normal. His lactate dehydrogenase (LDH) was elevated at 992 IU/L and creatine kinase was markedly elevated at 4,215 U/L. His HCV RNA by polymerase chain reaction was not detected.

While we were waiting for the lab results, he underwent bilateral lower-extremity venous Doppler to assess for a possible deep vein thrombosis (DVT). The Doppler study was negative. A chest X-ray was unremarkable. His O 2 saturation was 98%. Vital signs were stable. A brief initial neurologic exam was notable for decreased patellar reflexes, and marked loss of strength in both the upper and lower extremities. His gait was unsteady. After the receipt of his creatine kinase level, he was admitted to the hospital for further evaluation and testing.

Differential Diagnosis

Initially, when the patient came to clinic we were worried about his shortness of breath and weakness. Top on the list of differential diagnoses were heart failure, pulmonary embolism and, possibly, bleeding. He was sent for a chest X-ray while we waited for labs to arrive. The complete blood count came back normal, followed shortly by the report of a normal chest X-ray and negative Doppler report. Additional concerns were related to the ascending weakness and possible Guillain-Barré syndrome. While arranging the echocardiogram, the patient’s creatine kinase value was received and he was admitted to the hospital for further evaluation of myositis.

Catherine T.
Frenette

Upon admission, further studies were done, including blood work for syphilis, HIV, autoimmune hepatitis, rheumatoid arthritis, a Quantiferon and a myositis panel — all of which were negative. A lumbar puncture was performed to rule out Guillain-Barré syndrome with negative cerebrospinal fluid analysis. A CT scan of the chest/abdomen/pelvis and an MRI of the lower extremities were negative for any acute abnormality. The echocardiogram did not show evidence of any valvular disease, pulmonary hypertension or congestive heart failure. The ejection fraction was 65.7%. The esophogram did not reveal stricture, mass, obstruction, hiatal hernia or reflux. The electromyogram was positive for inflammatory myopathy, electromyographically of moderate severity. A muscle biopsy was performed that was notable for inflammatory myopathy, active and chronic, with features consistent with inclusion body myositis. The patient was started on high-dose IV methylprednisolone sodium succinate and noticed an almost immediate improvement in his symptomatology.

Discussion

Interferon is a well-known immune system up-regulator that can exacerbate any autoimmune disorder. There are many case studies in the literature demonstrating that interferon can cause myositis, which can be simply defined as an inflammatory infiltrate of the skeletal muscle.

Inclusion body myositis is part of a group of inflammatory myopathies that result in proximal muscle weakness, muscle enzyme elevations (creatine kinase, LDH), and extramuscular manifestations such as fever, rash and weight loss. Myositis-specific antibodies are present in the serum in about 50% to 60% of the cases, and they are directed against proteins in the nucleus and cytoplasm. Sporadic inclusion body myositis is distinctive in that it involves symmetric or asymmetric involvement of proximal or distal muscles occurring after age 50 years in a male-to-female ratio of 3:1. Inclusion body myositis can have severe systemic effects. For example, when inclusion body myositis affects the gastrointestinal tract, dysphagia with solids and liquids may be a predominant feature. The pharynx and upper esophageal sphincter are composed of skeletal muscle and, thus, aspiration/aspiration pneumonia may be a possible complication of the disease. Both esophageal and gastric emptying may be delayed.

Patients will exhibit marked increases in both creatine kinase and LDH, which is consistent with muscle injury. Both ALT and AST levels will be high. The erythrocyte sedimentation rate and C-reactive protein may be increased. The mainstay of treatment includes corticosteroids.

Conclusion

When myositis occurs from interferon, the prognosis is good with resolution of the symptoms quickly noticeable after withdrawal of the interferon and with addition of corticosteroids. The prognosis is less favorable when the myositis is from other etiologies, especially inclusion body myositis. Our patient responded rapidly to prednisone, noting an almost immediate improvement in his symptoms. And, on a positive note, his HCV RNA remains undetectable, representing a virologic cure.

References:
Aisa Y. Intern Med. 2001;40:1109-1112.
Alric L. Rev Med Interne. 2000;21:542-546.
Anderlini P. Cancer. 1995;76:678-679.
Aouba A. Joint Bone Spine. 2011;78:94-97.
Arai H. Lancet. 1995;345:582.
Blasini AM. J Clin Rheumatol. 1996;2:236-237.
Colomba C. J Antimicrob Chemother. 2012;67:249-250.
Ebert EC. Aliment Pharmacol Ther. 2010;31:359-365.
Gabrielli M. Am J Gastroenterol. 2003;98:940.
Greenfield SM. BMJ. 1994;309:512.
Hauschild A. Br J Dermatol. 2001;144:215-216.
Horsmans Y. Lancet 1995;345:1236.
John A. Indian J Gastroenterol. 2007;26:147-148.
Matsuya M. Intern Med. 1994;33:806-808.
Meyer O. Joint Bone Spine. 2009;76:464-473.
Ozdag F. J Dermatolog Treat. 2001;12:167-169.
Ramos-Casals M. Rheumatology. 2003;42:818-828.
Reinhold U. Lancet. 1997;349:540-541.
Ueno Y. J Clin Rheumatol. 1996;2:236-237.
van Londen GJ. J Clin Oncol. 2001;19:3794.
Venezia G. Dig Liver Dis. 2005;37:882-885.
Warabi Y. Rinsho Shinkeigaku. 2004;44:609-614.
Weidensaul D. Arthritis Rheum. 1995;38:437-439.
For more information:
Andrea Scherschel, MSN, FNP, and William B. Minteer, BS, are from the department of gastroenterology and hepatology at Scripps Clinic in La Jolla, Calif. Catherine T. Frenette, MD, is from the department of organ transplant at Scripps Clinic and is a member of the HCV Next Editorial Board. Frenette can be reached at Scripps Green Hospital Center for Organ and Cell Transplantation, 10666 N. Torrey Pines Road N200, La Jolla, CA 92037; email: frenette.catherine@scrippshealth.org.
Disclosure: The authors report no relevant financial disclosures.