American Journal of Therapeutics 23, e617–e620 (2016)
Idiopathic Nonviral Cryoglobulinemia Treated Successfully With Rituximab Mahmoud Kamel, MD,1* Bijin Thajudeen, MD,1 Erika Bracamonte, MD,2 and Machaiah Madhrira, MD1
Cryoglobulinemia is a systemic inflammatory syndrome that generally involves small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. The therapeutic management of idiopathic cryoglobulinemic vasculitis has yet to be defined because no study has evaluated the best strategies. However, treatment of severe vasculitis is traditionally based on a combination of corticosteroids and immunosuppressants or plasmapheresis, and more recently rituximab. We report a case of 77-year-old female patient diagnosed with idiopathic cryoglobulinemia, treated successfully with 6 months prednisone tapering and 2 doses of rituximab (1 g each dose). After receiving the abovementioned treatment, her creatinine went back to normal with resolution of proteinuria and hematuria, normalization of serum complements, and significant improvement in her clinical picture. We conclude that rituximab could be an effective treatment for idiopathic cryoglobulnemia. Keywords: acute kidney injury, cryoglobulinemia, rituximab
INTRODUCTION
CASE REPORT
Cryoglobulinemia is a systemic vasculitic disorder characterized by deposition of immune complexes in small- and medium-sized blood vessels.1 Treatment of severe vasculitis is traditionally based on targeting the pathogenic events by means of corticosteroids, immunosuppressors with or without plasmapheresis. These therapies can be associated with life-threatening complications, including infections and cytopenia. Rituximab has evolved as an effective and less toxic alternative for the treatment of cryoglobulinemia. In this study, we report a case diagnosed with idiopathic cryoglobulinemia, treated successfully with 6 months prednisone tapering and 2 doses of rituximab.
A 77-year-old female patient was seen by her primary care physician for nausea, vomiting, and generalized weakness. She also reported generalized joint pain and increased swelling in her lower limbs. She denied any abdominal pain, fever, chills, or change in bowel habits. There was also a history of recurrent skin rash, that comes and goes, for which she had a skin biopsy around 1 year ago, and she was told at that time that she has leukocytoclastic vasculitis. Routine blood test in her primary care physician’s office showed sodium 120, Cr 1.5 mg/dL for which she was admitted for further evaluation and treatment. Other significant medical history included hypertension, hyperlipidemia, and osteoporosis. Her medications include simvastatin, lisinopril, amlodipine, and ibandronate. She denied any history of smoking or alcohol use. There was no family history of renal disease. On admission, the body temperature was 37°C, pulse rate 74 beats/min, respiratory rate 18 breaths/min, and blood pressure 170/96 mm Hg. She was alert but seemed in distress due to nausea. There was no apparent skin rash or icterus. Chest examination showed
1
Division of Nephrology and 2Department of Pathology, University of Arizona, Tucson, AZ. The authors have no conflicts of interest to declare. *Address for correspondence: Division of Nephrology, University of Arizona, 1501, N Campbell Avenue, Tucson, AZ 85724. E-mail: [email protected]
1075–2765 Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e618
Kamel et al
good air entry with no added sounds, normal heart sounds. Abdominal examination showed no tenderness or organomegally. There was no renal angle tenderness. Bilateral lower extremities had 1+ pitting edema. The remainder of the examination was normal. Laboratory tests at admission were as shown in Table 1. Renal ultrasound showed normal sized kidney, increased echogenicity, and no hydronephrosis. In the background of leukocytoclastic vasculitis, a renal biopsy was performed, which showed hypercellular glomeruli and increased inflammatory cells, including neutrophils, as well as mesangial and endocapillary proliferation. Occasional cellular crescent formation is seen. Several glomeruli contain segmental Table 1. Serum and urine laboratory values at admission.
Laboratory results Hemoglobin, g/dL WBC, K/mL Platelet, K/mL Sodium, mMol/L Potassium, mMol/L Chloride, mMol/L CO2, mMol/L BUN, mg/dL Creatinine, mg/dL Albumin, gm/dL ALT, IU/L AST, IU/L Bilirubin, mg/dL Calcium, mg/dL Phosphorus, mg/dL C3, mg/dL C4, mg/dL ANA ANCA RF CCP Cryoglobulin Urine analysis
Value 12.5 11.1 158 117 4.1 90 16 32 1.5 2.6 35 24 0.7 8.5 4.5 62 ,3 Negative Negative Positive Negative Positive Protein 300 Specific gravity 1.009 WBC, 11; RBC, 56 No/RBC/WBC/ granular cast.
Reference range 11.5–15.5 3.4–10.4 150–425 136–145 3.5–5.1 101–111 23–25 7–20 0.6–1.1 3.4–4.8 0–55 5–34 0.2–1.2 8.6–10.6 2.3–4.7 83–193 15–57
WBC, white blood cell; BUN, blood urea nitrogen; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ANA, antinuclear antibody; ANCA, antinuclear cytoplasmic antibody; RF, rheumatoid factor; CCP, cyclic citrullinated peptide.
American Journal of Therapeutics (2016) 23(2)
hyaline thrombi and red cell fragments. There is patchy interstitial chronic inflammation, with diffuse interstitial edema and small scattered areas of fibrosis, as shown in (Figures 1, 2). After we discussed the case with the pathologist, our final impression was acute kidney injury secondary to cryoglobulinemic vasculitis. We decided to start patient on prednisone tapering, plasmapheresis (9 treatments) and 2 doses of rituximab (1000 mg each, 4 weeks in between). Her follow-up laboratory tests showed normalization of creatinine, complements, and significant improvement in her hematuria and proteinuria (as shown in Figure 3) in addition to significant improvement in her symptoms, including skin rash, joint pain, and poor appetite.
DISCUSSION CG consists of immunoglobulins (Igs) and complement components and precipitates on refrigeration of serum. The term cryoglobulinemia is often used to refer to a systemic inflammatory syndrome that generally involves small-to-medium vessel vasculitis due to CG-containing immune complexes.2,3 Hepatitis C virus infection is the most frequent cause of mixed cryoglobulinemia vasculitis (80%), whereas essential or idiopathic cryoglobulinemic vasculitis in the absence of identified etiologic factor represents less than 20%. CG syndromes are often classified as essential or secondary, based on the presence of underlying diseases.
FIGURE 1. Silver stain showing glomerulus with global hypercellularity and intracapillary material consistent with cryoglobulin (arrow). www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Idiopathic Cryoglobulinemia and Rituximab
FIGURE 2. H&E stain showed an arteriole with intraluminal, dense eosinophilc material (either fibrin or cryoglobulin).
According to Brouet classification, there are 3 types of cryogolbulinemia. Type 1: Monoclonal Ig (5%–25%) associated with paraproteinemia disorders. Type 2: Mixture of monoclonal/polyclonal (40%–60%) associated with viral infections (mainly hepatitis C). Type 3: Polyclonal Ig, associated with connective tissue disease. In type 2 CG (40%–60% of CG), there is a mixture of polyclonal Ig in association with a monoclonal Ig, typically IgM or IgA, with rheumatoid factor activity. Essential or idiopathic mixed cryoglobulinemia refers to those cases where secondary causes cannot be identified.
e619
Type 1 CG is often asymptomatic but also classically produces signs related to hyperviscosity and/or thrombosis, such as Raynaud phenomenon, digital ischemia, livedo reticularis, purpura, and neurologic symptoms. In contrast, mixed type 2 CGs most often produce constitutional and nonspecific symptoms, such as arthralgias, fatigue, and myalgias, as well as palpable purpura due to cutaneous vasculitis and sensory changes or weakness due to peripheral neuropathy. Aggressive therapy in idiopathic mixed cryoglobulinemia is primarily reserved for patients with acute severe disease, as manifested by progressive renal failure, distal necrosis requiring amputation, or advanced neuropathy. Treatment of hepatitis C–related cryoglobulinemia based on treatment of hepatitis C with ribavarin and interferon a in addition to plasmapheresis (a reasonable prescription is 1 plasma volume 3 times weekly for 2–3 weeks).4,5 Patients whose manifestations of mixed cryoglobulinemia are not controlled by, or are not appropriate for, the treatment previously mentioned, may respond to rituximab.6–9 The management of nonviral cryoglobulinemia vasculitis has yet to be defined, although it is traditionally based on a combination of corticosteroids and immunosuppressants or plasmapheresis. However, the results of these treatments are often disappointing. Data on the efficacy and safety of rituximab in nonviral cryoglobulinemia vasculitis are scarce, because only a few case reports have been reported in the literature. We decided to treat our patient with rituximab based on the results of a French study,10 which showed efficacy of rituxmab in treating nonviral cryoglobulinemia where 23 patients diagnosed with nonviral cryoglobulinemia were treated with rituximab (either 4 doses of 375 mg/m2 or 2 doses of 1 gm). Seventeen patients
FIGURE 3. Showed trend of serum Cr over 12 months. Zero time represents the time of admission to hospital. www.americantherapeutics.com
American Journal of Therapeutics (2016) 23(2)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e620
(85%) had a clinical complete response, and 3 patients (15%) had a partial response. Eight patients had immunological complete response, 6 had partial response, and 2 had no response. Ten patients with a follow-up of 6 months experienced a relapse after a median time of 13.5 months (range, 6–36 months) after the last rituximab infusion. Nine of these clinical relapsers were retreated with rituximab, and a response (complete or partial response) was noted in 7 (88%) of 8 patients (not assessable in 1 patient).
CONCLUSIONS Rituximab could be an effective treatment for idiopathic cryoglobulinemia. The interest of rituximab as first-line or salvage therapy for essential mixed cryoglobulinemia needs to be evaluated in randomized controlled trials.
REFERENCES 1. Trejo O, Ramos-Casals M, Garcia-Carrasco M, et al. Cryoglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine (Baltimore). 2001;80:252–262. 2. Gorevic PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med. 1980;69:287–308.
American Journal of Therapeutics (2016) 23(2)
Kamel et al 3. Brouet JC, Clauvel JP, Danon F, et al. Biologic and clinical significance of cryoglobulins: a report of 86 cases. Am J Med. 1974;57:775–788. 4. Saadoun D, Delluc A, Piette JC, et al. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol. 2008;20:23–28. 5. Terrier B, Saadoun D, Sene D, et al. Efficacy and tolerability of rituximab with or without PEGylated interferon alfa-2b plus ribavirin in severe hepatitis C virus–related vasculitis: a long-term followup study of thirty-two patients. Arthritis Rheum. 2009;60:2531–2540. 6. Zaja F, De Vita S, Mazzaro C, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood. 2003; 101:3827–3834. 7. Sansonno D, De Re V, Lauletta G, et al. Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon a with an anti-CD20. Blood. 2003; 101:3818–3826. 8. Roccatello D, Baldovino S, Rossi D, et al. Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant. 2004;19:3054–3061. 9. Cacoub P, Delluc A, Saadoun D, et al. Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand? Ann Rheum Dis. 2008; 67:283–287. 10. Terrier B, Launary D, Kaplanski G, et al. Safety and efficacy of rituximab in nonviral cryoglobulinemia vasculitis: data from the French Autoimmunity and Rituximab registry. Arthritis Care Res (Hoboken). 2010;62:1787–1795. doi:10.1002/acr.20318.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Idiopathic Nonviral Cryoglobulinemia Treated Successfully With Rituximab Mahmoud Kamel, MD,1* Bijin Thajudeen, MD,1 Erika Bracamonte, MD,2 and Machaiah Madhrira, MD1
Cryoglobulinemia is a systemic inflammatory syndrome that generally involves small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. The therapeutic management of idiopathic cryoglobulinemic vasculitis has yet to be defined because no study has evaluated the best strategies. However, treatment of severe vasculitis is traditionally based on a combination of corticosteroids and immunosuppressants or plasmapheresis, and more recently rituximab. We report a case of 77-year-old female patient diagnosed with idiopathic cryoglobulinemia, treated successfully with 6 months prednisone tapering and 2 doses of rituximab (1 g each dose). After receiving the abovementioned treatment, her creatinine went back to normal with resolution of proteinuria and hematuria, normalization of serum complements, and significant improvement in her clinical picture. We conclude that rituximab could be an effective treatment for idiopathic cryoglobulnemia. Keywords: acute kidney injury, cryoglobulinemia, rituximab
INTRODUCTION
CASE REPORT
Cryoglobulinemia is a systemic vasculitic disorder characterized by deposition of immune complexes in small- and medium-sized blood vessels.1 Treatment of severe vasculitis is traditionally based on targeting the pathogenic events by means of corticosteroids, immunosuppressors with or without plasmapheresis. These therapies can be associated with life-threatening complications, including infections and cytopenia. Rituximab has evolved as an effective and less toxic alternative for the treatment of cryoglobulinemia. In this study, we report a case diagnosed with idiopathic cryoglobulinemia, treated successfully with 6 months prednisone tapering and 2 doses of rituximab.
A 77-year-old female patient was seen by her primary care physician for nausea, vomiting, and generalized weakness. She also reported generalized joint pain and increased swelling in her lower limbs. She denied any abdominal pain, fever, chills, or change in bowel habits. There was also a history of recurrent skin rash, that comes and goes, for which she had a skin biopsy around 1 year ago, and she was told at that time that she has leukocytoclastic vasculitis. Routine blood test in her primary care physician’s office showed sodium 120, Cr 1.5 mg/dL for which she was admitted for further evaluation and treatment. Other significant medical history included hypertension, hyperlipidemia, and osteoporosis. Her medications include simvastatin, lisinopril, amlodipine, and ibandronate. She denied any history of smoking or alcohol use. There was no family history of renal disease. On admission, the body temperature was 37°C, pulse rate 74 beats/min, respiratory rate 18 breaths/min, and blood pressure 170/96 mm Hg. She was alert but seemed in distress due to nausea. There was no apparent skin rash or icterus. Chest examination showed
1
Division of Nephrology and 2Department of Pathology, University of Arizona, Tucson, AZ. The authors have no conflicts of interest to declare. *Address for correspondence: Division of Nephrology, University of Arizona, 1501, N Campbell Avenue, Tucson, AZ 85724. E-mail: [email protected]
1075–2765 Copyright Ó 2014 Wolters Kluwer Health, Inc. All rights reserved.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e618
Kamel et al
good air entry with no added sounds, normal heart sounds. Abdominal examination showed no tenderness or organomegally. There was no renal angle tenderness. Bilateral lower extremities had 1+ pitting edema. The remainder of the examination was normal. Laboratory tests at admission were as shown in Table 1. Renal ultrasound showed normal sized kidney, increased echogenicity, and no hydronephrosis. In the background of leukocytoclastic vasculitis, a renal biopsy was performed, which showed hypercellular glomeruli and increased inflammatory cells, including neutrophils, as well as mesangial and endocapillary proliferation. Occasional cellular crescent formation is seen. Several glomeruli contain segmental Table 1. Serum and urine laboratory values at admission.
Laboratory results Hemoglobin, g/dL WBC, K/mL Platelet, K/mL Sodium, mMol/L Potassium, mMol/L Chloride, mMol/L CO2, mMol/L BUN, mg/dL Creatinine, mg/dL Albumin, gm/dL ALT, IU/L AST, IU/L Bilirubin, mg/dL Calcium, mg/dL Phosphorus, mg/dL C3, mg/dL C4, mg/dL ANA ANCA RF CCP Cryoglobulin Urine analysis
Value 12.5 11.1 158 117 4.1 90 16 32 1.5 2.6 35 24 0.7 8.5 4.5 62 ,3 Negative Negative Positive Negative Positive Protein 300 Specific gravity 1.009 WBC, 11; RBC, 56 No/RBC/WBC/ granular cast.
Reference range 11.5–15.5 3.4–10.4 150–425 136–145 3.5–5.1 101–111 23–25 7–20 0.6–1.1 3.4–4.8 0–55 5–34 0.2–1.2 8.6–10.6 2.3–4.7 83–193 15–57
WBC, white blood cell; BUN, blood urea nitrogen; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ANA, antinuclear antibody; ANCA, antinuclear cytoplasmic antibody; RF, rheumatoid factor; CCP, cyclic citrullinated peptide.
American Journal of Therapeutics (2016) 23(2)
hyaline thrombi and red cell fragments. There is patchy interstitial chronic inflammation, with diffuse interstitial edema and small scattered areas of fibrosis, as shown in (Figures 1, 2). After we discussed the case with the pathologist, our final impression was acute kidney injury secondary to cryoglobulinemic vasculitis. We decided to start patient on prednisone tapering, plasmapheresis (9 treatments) and 2 doses of rituximab (1000 mg each, 4 weeks in between). Her follow-up laboratory tests showed normalization of creatinine, complements, and significant improvement in her hematuria and proteinuria (as shown in Figure 3) in addition to significant improvement in her symptoms, including skin rash, joint pain, and poor appetite.
DISCUSSION CG consists of immunoglobulins (Igs) and complement components and precipitates on refrigeration of serum. The term cryoglobulinemia is often used to refer to a systemic inflammatory syndrome that generally involves small-to-medium vessel vasculitis due to CG-containing immune complexes.2,3 Hepatitis C virus infection is the most frequent cause of mixed cryoglobulinemia vasculitis (80%), whereas essential or idiopathic cryoglobulinemic vasculitis in the absence of identified etiologic factor represents less than 20%. CG syndromes are often classified as essential or secondary, based on the presence of underlying diseases.
FIGURE 1. Silver stain showing glomerulus with global hypercellularity and intracapillary material consistent with cryoglobulin (arrow). www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Idiopathic Cryoglobulinemia and Rituximab
FIGURE 2. H&E stain showed an arteriole with intraluminal, dense eosinophilc material (either fibrin or cryoglobulin).
According to Brouet classification, there are 3 types of cryogolbulinemia. Type 1: Monoclonal Ig (5%–25%) associated with paraproteinemia disorders. Type 2: Mixture of monoclonal/polyclonal (40%–60%) associated with viral infections (mainly hepatitis C). Type 3: Polyclonal Ig, associated with connective tissue disease. In type 2 CG (40%–60% of CG), there is a mixture of polyclonal Ig in association with a monoclonal Ig, typically IgM or IgA, with rheumatoid factor activity. Essential or idiopathic mixed cryoglobulinemia refers to those cases where secondary causes cannot be identified.
e619
Type 1 CG is often asymptomatic but also classically produces signs related to hyperviscosity and/or thrombosis, such as Raynaud phenomenon, digital ischemia, livedo reticularis, purpura, and neurologic symptoms. In contrast, mixed type 2 CGs most often produce constitutional and nonspecific symptoms, such as arthralgias, fatigue, and myalgias, as well as palpable purpura due to cutaneous vasculitis and sensory changes or weakness due to peripheral neuropathy. Aggressive therapy in idiopathic mixed cryoglobulinemia is primarily reserved for patients with acute severe disease, as manifested by progressive renal failure, distal necrosis requiring amputation, or advanced neuropathy. Treatment of hepatitis C–related cryoglobulinemia based on treatment of hepatitis C with ribavarin and interferon a in addition to plasmapheresis (a reasonable prescription is 1 plasma volume 3 times weekly for 2–3 weeks).4,5 Patients whose manifestations of mixed cryoglobulinemia are not controlled by, or are not appropriate for, the treatment previously mentioned, may respond to rituximab.6–9 The management of nonviral cryoglobulinemia vasculitis has yet to be defined, although it is traditionally based on a combination of corticosteroids and immunosuppressants or plasmapheresis. However, the results of these treatments are often disappointing. Data on the efficacy and safety of rituximab in nonviral cryoglobulinemia vasculitis are scarce, because only a few case reports have been reported in the literature. We decided to treat our patient with rituximab based on the results of a French study,10 which showed efficacy of rituxmab in treating nonviral cryoglobulinemia where 23 patients diagnosed with nonviral cryoglobulinemia were treated with rituximab (either 4 doses of 375 mg/m2 or 2 doses of 1 gm). Seventeen patients
FIGURE 3. Showed trend of serum Cr over 12 months. Zero time represents the time of admission to hospital. www.americantherapeutics.com
American Journal of Therapeutics (2016) 23(2)
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
e620
(85%) had a clinical complete response, and 3 patients (15%) had a partial response. Eight patients had immunological complete response, 6 had partial response, and 2 had no response. Ten patients with a follow-up of 6 months experienced a relapse after a median time of 13.5 months (range, 6–36 months) after the last rituximab infusion. Nine of these clinical relapsers were retreated with rituximab, and a response (complete or partial response) was noted in 7 (88%) of 8 patients (not assessable in 1 patient).
CONCLUSIONS Rituximab could be an effective treatment for idiopathic cryoglobulinemia. The interest of rituximab as first-line or salvage therapy for essential mixed cryoglobulinemia needs to be evaluated in randomized controlled trials.
REFERENCES 1. Trejo O, Ramos-Casals M, Garcia-Carrasco M, et al. Cryoglobulinemia: study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine (Baltimore). 2001;80:252–262. 2. Gorevic PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinemia: clinical aspects and long-term follow-up of 40 patients. Am J Med. 1980;69:287–308.
American Journal of Therapeutics (2016) 23(2)
Kamel et al 3. Brouet JC, Clauvel JP, Danon F, et al. Biologic and clinical significance of cryoglobulins: a report of 86 cases. Am J Med. 1974;57:775–788. 4. Saadoun D, Delluc A, Piette JC, et al. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol. 2008;20:23–28. 5. Terrier B, Saadoun D, Sene D, et al. Efficacy and tolerability of rituximab with or without PEGylated interferon alfa-2b plus ribavirin in severe hepatitis C virus–related vasculitis: a long-term followup study of thirty-two patients. Arthritis Rheum. 2009;60:2531–2540. 6. Zaja F, De Vita S, Mazzaro C, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood. 2003; 101:3827–3834. 7. Sansonno D, De Re V, Lauletta G, et al. Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon a with an anti-CD20. Blood. 2003; 101:3818–3826. 8. Roccatello D, Baldovino S, Rossi D, et al. Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant. 2004;19:3054–3061. 9. Cacoub P, Delluc A, Saadoun D, et al. Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: where do we stand? Ann Rheum Dis. 2008; 67:283–287. 10. Terrier B, Launary D, Kaplanski G, et al. Safety and efficacy of rituximab in nonviral cryoglobulinemia vasculitis: data from the French Autoimmunity and Rituximab registry. Arthritis Care Res (Hoboken). 2010;62:1787–1795. doi:10.1002/acr.20318.
www.americantherapeutics.com
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
