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Limb-Threatening Arterial Thrombosis in a Patient with Eosinophilic Granulomatosis with Polyangiitis
Journal of the American College of Clinical Wound Specialists (2017) -, -–-
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Limb-Threatening Arterial Thrombosis in a Patient with Eosinophilic Granulomatosis with Polyangiitis Taylor Braunberger, MDa,1, Jessica S. Mounessa, BSb,1, Ryan O’Leary, MDb, Ekama Carlson, MD, PhDb, Sabrina Newman, MDb,* a b
University of North Dakota, Fargo, ND, USA; and University of Colorado Hospital, Aurora, CO, USA KEYWORDS: Eosinophilic granulomatosis with polyangiitis; Churg-Strauss syndrome; Thrombosis; P-ANCA; Gangrene
Abstract Eosinophilic granulomatosis (EGPA), or Churg-Strauss syndrome, is a rare and necrotizing systemic vasculitis, which affects small-to-medium-sized vessels and often manifests with severe asthma and eosinophilia. We report a case of a 72 year-old male with a two-year lung-biopsy proven history of EGPA who presented with retiform purpura and patchy necrosis on his bilateral shins, which progressed to sharply demarcated, stellate ulcerations with surrounding erythema within two weeks. Laboratory work up revealed elevated anti-Cardiolipin IgM, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein, although P-neutrophil cytoplasmic antibody (P-ANCA) and C-neutrophil cytoplasmic antibody (C-ANCA) were negative. Vascular studies revealed long anterior tibial and dorsalis pedis artery occlusion and severe small vessel disease in plantar digital arteries. Despite treatment with intravenous cyclophosphamide, pulse-dose methylprednisolone, and pentoxifylline, the patient experienced disease progression and limb threatening arterial thrombosis. This case highlights the importance of vascular and neuropathic sequelae that may result from untreated or undertreated EGPA in P-ANCA-negative patients without active pulmonary symptoms. Ó 2017 Elsevier Inc. All rights reserved.
Case A 72 year-old male with a history of eosinophilic granulomatosis with polyangiitis (EGPA), hypothyroidism, and corticosteroid-induced diabetes mellitus presented with worsening lower extremity skin lesions. Fifteen months Financial disclosures: None. Conflicts of interest: None. 1 Taylor Braunberger and Jessica Mounessa contributed equally to this publication. * Corresponding author. University of Colorado Hospital, 1665 Aurora Ct, Aurora, CO 80045, USA. Fax: 11 720 848 0529. E-mail address: [email protected]
prior to presentation, he developed refractory asthma with associated weight loss and fevers. A diagnosis of EGPA was made via lung biopsy. Treatment was initiated with 80 mg methylprednisolone daily and three 1500 mg boluses of cyclophosphamide over two months. The steroid dose was tapered and he was subsequently maintained on 10 mg of prednisone daily. Although his pulmonary symptoms improved, he developed progressive loss of sensation and intermittent purpuric eruptions and erosions in his bilateral lower extremities while on maintenance low dose prednisone therapy. Three months prior to presentation, he underwent a right partial second toe amputation in the setting of dry gangrene for occluded right anterior tibial artery.
2213-5103/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jccw.2017.03.001
CRP 5.4.0 DTD - JCCW69_proof - 11 April 2017 - 4:46 pm - ce
59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121
2
Initial physical examination revealed purpuric dermal plaques bilaterally on the patient’s distal lower extremities. His shins and calves demonstrated retiform purpura and patchy necrosis, livedo racemosa, and hemorrhagic vesicles bilaterally. Over the course of two weeks, these progressed to sharply demarcated, stellate ulcerations with surrounding erythema (Fig. 1). Laboratory findings revealed elevated erythrocyte sedimentation rate (97 mm/h) and C-reactive protein (100 mg/ mL) with an absolute eosinophil count within normal limits. Anti-cardiolipin IgM antibody was elevated at 26. Thrombotic and vasculopathy work up revealed negative lupus anticoagulant and anti-cardiolipin IgG antibody, ruling out the presence of antiphospholipid syndrome. Immunology work up including P-neutrophil cytoplasmic antibody (P-ANCA) and C-neutrophil cytoplasmic antibody (C-ANCA) was negative except for low Complement4 (C4), borderline ANA (1:160 titer), and elevated Rheumatoid Factor (.600 IU/mL). Vascular studies (lower extremities arterial pressures and pulsed volume recording doppler) revealed long anterior tibial and dorsalis pedis artery occlusion and severe small vessel disease in plantar digital arteries. Punch biopsy of the edge of a retiform plaque on his left ankle revealed necrotic epithelium and eccrine coils, consistent with infarcted skin. Treatment included a 1500 mg bolus of intravenous cyclophosphamide, 250 mg pulse-dose intravenous methylprednisolone every 6 h for 72 h, and 400 mg oral pentoxifylline three times daily. A maintenance dose of 30 mg of prednisone twice daily was later initiated. His initial lesions quickly progressed to dry gangrene over his right third and fourth toes, as well as his left first through fourth toes over the course of two weeks (Fig. 1).
Discussion The differential diagnosis for dermal vascular compromise and accompanying cutaneous necrosis includes vasculitis, vasculopathy, non-uremic calciphylaxis, or angioinvasive
infections.1 Our extensive work up revealed that inadequate treatment with only low dose prednisone in our patient with biopsy-proven EGPA led to disease progression and limb threatening arterial thrombosis. The proposed mechanism of thrombosis in EGPA involves increased eosinophils, which produce both cationic proteins and tissue factor (TF).2 Cationic proteins including major basic protein, eosinophil cationic protein, and eosinophil peroxidase inhibit natural anticoagulant factors in the clotting cascade, while TF directly initiates the clotting cascade.2 In Ames et al’s 2010 review, a total of 12 arterial and 12 venous thrombosis cases were reported. Every patient noted to have a thrombotic event either had an unreported or negative P-ANCA.2 Recent studies reveal that P-ANCA negative patients tend to have a much higher tissue infiltration by eosinophils.3 During their tissue migration, eosinophils may be maximally thrombogenic.4 Thus, P-ANCA negative EGPA patients may demonstrate a higher risk for thrombosis. At the same time, EGPA only results in vascular occlusion and arterial thrombi in rare cases.2 Typically, the disease presents with asthma, allergic rhinitis, and sinusitis. Patients subsequently develop eosinophilia, and later vasculitis.5 Patients with uncomplicated EGPA initially receive low dose prednisone at 0.5–1.5 mg/kg/ day.6,7 Those refractory to steroids or with major organ involvement are treated with corticosteroids in combination with an immunosuppressant such as cyclophosphamide.6,7 Neurologic symptoms, which affect 60–70% of patients,8 may indicate disease progression resulting from the effect of the disease on the microcirculation.2 P-ANCA negative EGPA patients may benefit from thromboprophylaxis as they experience a higher risk of thrombosis. Although the association between P-ANCA and EGPA exists, a recent study revealed that only half of EGPA patients test positive for P-ANCA. P-ANCA positivity is less commonly linked to cutaneous lesions and cardiovascular involvement of EGPA.9 Our review highlights the importance of vascular and neuropathic sequelae that can occur with untreated or undertreated EGPA in the absence
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Journal of the American College of Clinical Wound Specialists, Vol -, No -
Figure 1 (a): Lower extremities of patient upon initial presentation to Dermatology. Retiform purpura, patchy necrosis, livedo racemosa, palpable purpura, and hemorrhagic vesicles bilaterally. (b): Lower extremities of patient two weeks later. Sharply demarcated, stellate ulcerations with mild surrounding erythema.
CRP 5.4.0 DTD - JCCW69_proof - 11 April 2017 - 4:46 pm - ce
185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247
Braunberger et al 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310
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of P-ANCA-positivity and lack of active pulmonary symptoms.
References 1. Masi AT, Hunder GG, Lie JT, et al: The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33(8): 1094–1100. 2. Ames PR, Margaglione M, Mackie S, Alves JD: Eosinophilia and thrombophilia in churg strauss syndrome: a clinical and pathogenetic overview. Clin Appl Thromb Hemost. 2010;16(6): 628–636. 3. Isa H, Lightman S, Luthert PJ, Rose GE, Verity DH, Taylor SR: Histopathological features predictive of a clinical diagnosis of ophthalmic granulomatosis with polyangiitis (GPA). Int J Clin Exp Pathol. 2012; 5(7):684–689.
4. Khoury P, Grayson PC, Klion AD: Eosinophils in vasculitis: characteristics and roles in pathogenesis. Nat Rev Rheumatol. 2014;10(8): 474–483. 5. Marzano AV, Tedeschi A, Rossio R, Fanoni D, Cugno M: Prothrombotic state in Churg-Strauss syndrome: a case report. J Investig Allergol Clin Immunol. 2010;20(7):616–619. 6. Pagnoux C, Groh M: Optimal therapy and prospects for new medicines in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Expert Rev Clin Immunol. 2016;12(10):1059–1067. 7. Pagnoux C, Guilpain P, Guillevin L: Churg-Strauss syndrome. Curr Opin Rheumatol. 2007;19(1):25–32. 8. Santos-Pinheiro F, Li Y: Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) presenting with polyneuropathy – a case series. J Clin Neuromuscul Dis. 2015;16(3):125–130. 9. Sada KE, Amano K, Uehara R, et al: A nationwide survey on the epidemiology and clinical features of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) in Japan. Modern Rheumatol Jpn Rheum Assoc. 2014;24(4):640–644.
CRP 5.4.0 DTD - JCCW69_proof - 11 April 2017 - 4:46 pm - ce
Q3
311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373
1 2 3 4 5 6 7 8 9 10 Q1 11 12 13 14 Q2 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58
Limb-Threatening Arterial Thrombosis in a Patient with Eosinophilic Granulomatosis with Polyangiitis Taylor Braunberger, MDa,1, Jessica S. Mounessa, BSb,1, Ryan O’Leary, MDb, Ekama Carlson, MD, PhDb, Sabrina Newman, MDb,* a b
University of North Dakota, Fargo, ND, USA; and University of Colorado Hospital, Aurora, CO, USA KEYWORDS: Eosinophilic granulomatosis with polyangiitis; Churg-Strauss syndrome; Thrombosis; P-ANCA; Gangrene
Abstract Eosinophilic granulomatosis (EGPA), or Churg-Strauss syndrome, is a rare and necrotizing systemic vasculitis, which affects small-to-medium-sized vessels and often manifests with severe asthma and eosinophilia. We report a case of a 72 year-old male with a two-year lung-biopsy proven history of EGPA who presented with retiform purpura and patchy necrosis on his bilateral shins, which progressed to sharply demarcated, stellate ulcerations with surrounding erythema within two weeks. Laboratory work up revealed elevated anti-Cardiolipin IgM, rheumatoid factor, erythrocyte sedimentation rate, and C-reactive protein, although P-neutrophil cytoplasmic antibody (P-ANCA) and C-neutrophil cytoplasmic antibody (C-ANCA) were negative. Vascular studies revealed long anterior tibial and dorsalis pedis artery occlusion and severe small vessel disease in plantar digital arteries. Despite treatment with intravenous cyclophosphamide, pulse-dose methylprednisolone, and pentoxifylline, the patient experienced disease progression and limb threatening arterial thrombosis. This case highlights the importance of vascular and neuropathic sequelae that may result from untreated or undertreated EGPA in P-ANCA-negative patients without active pulmonary symptoms. Ó 2017 Elsevier Inc. All rights reserved.
Case A 72 year-old male with a history of eosinophilic granulomatosis with polyangiitis (EGPA), hypothyroidism, and corticosteroid-induced diabetes mellitus presented with worsening lower extremity skin lesions. Fifteen months Financial disclosures: None. Conflicts of interest: None. 1 Taylor Braunberger and Jessica Mounessa contributed equally to this publication. * Corresponding author. University of Colorado Hospital, 1665 Aurora Ct, Aurora, CO 80045, USA. Fax: 11 720 848 0529. E-mail address: [email protected]
prior to presentation, he developed refractory asthma with associated weight loss and fevers. A diagnosis of EGPA was made via lung biopsy. Treatment was initiated with 80 mg methylprednisolone daily and three 1500 mg boluses of cyclophosphamide over two months. The steroid dose was tapered and he was subsequently maintained on 10 mg of prednisone daily. Although his pulmonary symptoms improved, he developed progressive loss of sensation and intermittent purpuric eruptions and erosions in his bilateral lower extremities while on maintenance low dose prednisone therapy. Three months prior to presentation, he underwent a right partial second toe amputation in the setting of dry gangrene for occluded right anterior tibial artery.
2213-5103/$ - see front matter Ó 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jccw.2017.03.001
CRP 5.4.0 DTD - JCCW69_proof - 11 April 2017 - 4:46 pm - ce
59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121
2
Initial physical examination revealed purpuric dermal plaques bilaterally on the patient’s distal lower extremities. His shins and calves demonstrated retiform purpura and patchy necrosis, livedo racemosa, and hemorrhagic vesicles bilaterally. Over the course of two weeks, these progressed to sharply demarcated, stellate ulcerations with surrounding erythema (Fig. 1). Laboratory findings revealed elevated erythrocyte sedimentation rate (97 mm/h) and C-reactive protein (100 mg/ mL) with an absolute eosinophil count within normal limits. Anti-cardiolipin IgM antibody was elevated at 26. Thrombotic and vasculopathy work up revealed negative lupus anticoagulant and anti-cardiolipin IgG antibody, ruling out the presence of antiphospholipid syndrome. Immunology work up including P-neutrophil cytoplasmic antibody (P-ANCA) and C-neutrophil cytoplasmic antibody (C-ANCA) was negative except for low Complement4 (C4), borderline ANA (1:160 titer), and elevated Rheumatoid Factor (.600 IU/mL). Vascular studies (lower extremities arterial pressures and pulsed volume recording doppler) revealed long anterior tibial and dorsalis pedis artery occlusion and severe small vessel disease in plantar digital arteries. Punch biopsy of the edge of a retiform plaque on his left ankle revealed necrotic epithelium and eccrine coils, consistent with infarcted skin. Treatment included a 1500 mg bolus of intravenous cyclophosphamide, 250 mg pulse-dose intravenous methylprednisolone every 6 h for 72 h, and 400 mg oral pentoxifylline three times daily. A maintenance dose of 30 mg of prednisone twice daily was later initiated. His initial lesions quickly progressed to dry gangrene over his right third and fourth toes, as well as his left first through fourth toes over the course of two weeks (Fig. 1).
Discussion The differential diagnosis for dermal vascular compromise and accompanying cutaneous necrosis includes vasculitis, vasculopathy, non-uremic calciphylaxis, or angioinvasive
infections.1 Our extensive work up revealed that inadequate treatment with only low dose prednisone in our patient with biopsy-proven EGPA led to disease progression and limb threatening arterial thrombosis. The proposed mechanism of thrombosis in EGPA involves increased eosinophils, which produce both cationic proteins and tissue factor (TF).2 Cationic proteins including major basic protein, eosinophil cationic protein, and eosinophil peroxidase inhibit natural anticoagulant factors in the clotting cascade, while TF directly initiates the clotting cascade.2 In Ames et al’s 2010 review, a total of 12 arterial and 12 venous thrombosis cases were reported. Every patient noted to have a thrombotic event either had an unreported or negative P-ANCA.2 Recent studies reveal that P-ANCA negative patients tend to have a much higher tissue infiltration by eosinophils.3 During their tissue migration, eosinophils may be maximally thrombogenic.4 Thus, P-ANCA negative EGPA patients may demonstrate a higher risk for thrombosis. At the same time, EGPA only results in vascular occlusion and arterial thrombi in rare cases.2 Typically, the disease presents with asthma, allergic rhinitis, and sinusitis. Patients subsequently develop eosinophilia, and later vasculitis.5 Patients with uncomplicated EGPA initially receive low dose prednisone at 0.5–1.5 mg/kg/ day.6,7 Those refractory to steroids or with major organ involvement are treated with corticosteroids in combination with an immunosuppressant such as cyclophosphamide.6,7 Neurologic symptoms, which affect 60–70% of patients,8 may indicate disease progression resulting from the effect of the disease on the microcirculation.2 P-ANCA negative EGPA patients may benefit from thromboprophylaxis as they experience a higher risk of thrombosis. Although the association between P-ANCA and EGPA exists, a recent study revealed that only half of EGPA patients test positive for P-ANCA. P-ANCA positivity is less commonly linked to cutaneous lesions and cardiovascular involvement of EGPA.9 Our review highlights the importance of vascular and neuropathic sequelae that can occur with untreated or undertreated EGPA in the absence
print & web 4C=FPO
122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184
Journal of the American College of Clinical Wound Specialists, Vol -, No -
Figure 1 (a): Lower extremities of patient upon initial presentation to Dermatology. Retiform purpura, patchy necrosis, livedo racemosa, palpable purpura, and hemorrhagic vesicles bilaterally. (b): Lower extremities of patient two weeks later. Sharply demarcated, stellate ulcerations with mild surrounding erythema.
CRP 5.4.0 DTD - JCCW69_proof - 11 April 2017 - 4:46 pm - ce
185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247
Braunberger et al 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310
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3
of P-ANCA-positivity and lack of active pulmonary symptoms.
References 1. Masi AT, Hunder GG, Lie JT, et al: The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33(8): 1094–1100. 2. Ames PR, Margaglione M, Mackie S, Alves JD: Eosinophilia and thrombophilia in churg strauss syndrome: a clinical and pathogenetic overview. Clin Appl Thromb Hemost. 2010;16(6): 628–636. 3. Isa H, Lightman S, Luthert PJ, Rose GE, Verity DH, Taylor SR: Histopathological features predictive of a clinical diagnosis of ophthalmic granulomatosis with polyangiitis (GPA). Int J Clin Exp Pathol. 2012; 5(7):684–689.
4. Khoury P, Grayson PC, Klion AD: Eosinophils in vasculitis: characteristics and roles in pathogenesis. Nat Rev Rheumatol. 2014;10(8): 474–483. 5. Marzano AV, Tedeschi A, Rossio R, Fanoni D, Cugno M: Prothrombotic state in Churg-Strauss syndrome: a case report. J Investig Allergol Clin Immunol. 2010;20(7):616–619. 6. Pagnoux C, Groh M: Optimal therapy and prospects for new medicines in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Expert Rev Clin Immunol. 2016;12(10):1059–1067. 7. Pagnoux C, Guilpain P, Guillevin L: Churg-Strauss syndrome. Curr Opin Rheumatol. 2007;19(1):25–32. 8. Santos-Pinheiro F, Li Y: Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) presenting with polyneuropathy – a case series. J Clin Neuromuscul Dis. 2015;16(3):125–130. 9. Sada KE, Amano K, Uehara R, et al: A nationwide survey on the epidemiology and clinical features of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) in Japan. Modern Rheumatol Jpn Rheum Assoc. 2014;24(4):640–644.
CRP 5.4.0 DTD - JCCW69_proof - 11 April 2017 - 4:46 pm - ce
Q3
311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373