A Rare Case of Digital Ischemia and Gangrene in ANCA-Associated Vasculitis with Review of the Literature.
Antineutrophil Cytoplasmic Antibody- (ANCA-) associated vasculitis is a group of autoimmune small to medium vessel necrotizing vasculitides [1-6]. Granulomatosis with Polyangiitis (GPA), previously known as Wegener's, is a type of ANCA vasculitis that is usually associated with cANCA. The range of clinical manifestations of GPA can involve almost any organ system, but the classic organ systems involved include the upper respiratory tract, lower respiratory tract, and kidneys [1-6]. One of the rarer manifestations is digital ischemia and gangrene. We report a rare case of GPA presenting with digital ischemia and gangrene, with a review of the literature.
A 62-year-old male with a past medical history of hypertension and vitiligo presented to the hospital with 2 months of worsening left 1st toe, left 3rd finger, and right 2nd, 3rd, and 4th finger pain, swelling, and discoloration. The patient was a mechanic and endorsed an inciting traumatic event from dropping a heavy tool to his left 3rd finger and left 1st toe but denied any preceding trauma to the digits on his right hand. Soon after the initiation of the pain and swelling, there was also associated discoloration, with blue/black color changes with gradual scab formation.
On further review of systems, the patient reported several weeks of diffuse joint pains, intermittent eye pain and red eyes, hemoptysis, epistaxis, nasal congestion, and weight loss (unable to quantify but has decreased several belt notches). The patient otherwise denied any Raynaud's phenomenon, skin tightening, oral ulcerations, genital ulceration, chest pain, shortness of breath, abdominal pain, hematuria, ear pain, sinus pain, fevers, chills, night sweats, or smoking history.
The patient's initial vitals were significant for hypertension only. On physical exam, the patient was in no acute distress. The head and neck exam was notable for bilateral conjunctivitis (see Figure 1) and right nasal ulceration. The cardiopulmonary exam was notable for poor airflow on lung auscultation. The skin exam was notable for vitiligo. The musculoskeletal exam was significant for diffuse joint tenderness but no joint swelling/warmth. The extremity exam revealed 3+ pitting edema of his lower extremities, right 2nd/3rd/4th finger duskiness and necrosis (see Figures 2(a) and 2(b)), left 3rd finger duskiness and necrosis (see Figures 3(a) and 3(b)), and left 1st toe with duskiness and necrosis (see Figures 4(a) and 4(b)).
The admitting labs were notable for elevated creatinine (1.74 mg/dL [ref 0.6-1.3]), elevated alkaline phosphatase (180 units/L [ref 38-126]), elevated CRP (140 mg/L [ref 0.0-7.0]), elevated ESR (67 mm/hr [ref < 20]), leukocytosis (12.5 thousand cells/uL [ref 3.8-10.9]), and anemia (12.5 gm/dL [ref 13.6-17.3]). Urinalysis revealed the presence of large blood, red blood cells (113 cells/HPF [ref 0-3]), white blood cells (13 cells/HPF [ref 0-5]), protein (100 mg/dL [ref negative]), and cellular casts (4/LPF). Random urine protein/creatinine ratio was 0.959 gm/gm. Initial chest X-ray on admission showed patchy right upper lobe airspace disease.
Given both pulmonary and renal system involvement, there was concern for pulmonary-renal syndromes, including ANCA-associated vasculitides, antiglomerular basement membrane disease, systemic lupus erythematous, and cryoglobulinemia. Other vasculitides of consideration included polyarteritis nodosum and thromboangiitis obliterans. We also considered that prothrombotic disorders such as antiphospholipid syndrome and embolic phenomenon can occur with cholesterol emboli or atrial myxoma. Infectious etiologies were considered as well, including endocarditis with embolic phenomenon. A paraneoplastic syndrome from a malignancy was entertained as well.
Further investigation was pursued to workup the aforementioned etiologies, including more laboratory evaluation with serologies pertinent for positive c-ANCA (proteinase-3 Ab 3.1 AI [ref < 1.0]), positive rheumatoid factor (80 IU/mL [ref < 14]), negative ANA, negative antiglomerular basement membrane antibody, negative anti-SSA/SSB, negative cryoglobulin screen, negative lupus anticoagulant, negative anti-Beta2 glycoprotein, and negative anticardiolipin. The infectious laboratory workup included multiple blood cultures with no growth. Transthoracic echocardiography did not show any thrombus, valvular disease, or atrial myxoma. Additional imaging was pursued that included computer tomography of the chest, which demonstrated extensive consolidation with air bronchograms predominately involving the right upper lobe and some contiguous involvement of the right middle and lower lobes. Bronchoscopy with serial bronchial washings by pulmonary consultants was consistent with alveolar hemorrhage. The ocular examination by ophthalmology consultants was consistent with episcleritis.
The patient was diagnosed with ANCA-associated vasculitis. The defining pathological difference between Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA) is the presence of granulomatous changes on biopsy based on our current classification criteria [1-3]. To support the diagnosis, we were planning on a skin biopsy but the patient refused. A renal biopsy was scheduled but the patient did not show for the procedure. Often even if biopsies are performed, there is a risk of missing definitive granuloma tissue due to sampling error, which makes differentiating the type of ANCA-associated vasculitis difficult. Based on the recently presented ACR/EULAR Provisional 2017 Classification Criteria for GPA, the patient scores 4 points on clinical criteria given his bloody nasal discharge, sinonasal congestion, and red or painful eyes and scores 5 points on serologic criteria with a positive cANCA-PR3 antibody. A combined score of greater than or equal to 5 is needed for classification of GPA . The patient was classified as most likely having GPA and treated with IV methylprednisolone followed by oral prednisone, which was slowly tapered over the next several months. He was also started on monthly IV cyclophosphamide for a total of 6 months. The patient responded well to therapy with improvement of all of his organ dysfunction, including improvement of the reversible tissue ischemia, cessation of digital gangrenous extension, and eventual autoamputation of the irreversible gangrenous parts of his digits.
Based on our review of the English literature, to the best of our knowledge, only 16 cases have been previously reported describing adult patients with GPA who presented with digital ischemia and gangrene [7-20] (see Table 1). Given the paucity of cases reported, we suspect the prevalence with digital ischemia and gangrene in the GPA population to be <1%. All of the cases in this review, including our case, satisfy the ACR/EULAR Provisional 2017 Classification Criteria for GPA with the exception of the 58-year-old male, patient number 17, in the case series by Pinching et al. where not enough specific case details were reported to confirm the diagnosis. The mean age of patients was 46.9 years and included a range of 24-80 years. Including our patient, 12 of 17 were males (71%) compared to 5 of 17 females (29%). Most patients presented with multiorgan involvement including 14 of 17 with pulmonary involvement (82%), 11 of 17 with kidney disease (65%), and 13 of 17 with sinonasal disease (76%). cANCA was confirmed positive in 13 patients and negative in one patient, and the data was not available in 3 of the cases. Only 3 patients demonstrated granulomas on biopsy. Confounding risk factors were inconsistently reported but include a past medical history of HTN in three cases [9, 16, 19], DM in three cases [13, 15, 16], tobacco use in two cases [13, 18], and dyslipidemia in one case . The clinical phenotype usually involves multiple disparate digits. 10 of 17 cases described isolated involvement of the upper extremities (59%) compared to the 5 of 17 with isolated involvement of the lower extremities (29%). Only two cases (12%), including ours, have described simultaneous involvement of both the upper and lower extremities . The pathophysiology of the digital ischemia and gangrene is thought to be from destruction of medium sized vessels from active vasculitis, which has been demonstrated in case reports where histological examination of affected tissue showed arteritis [9, 15]. However, there is also evidence that in situ thrombosis, as a result of active vasculitis, can lead to ischemia and gangrene, as seen in angiographic examination of affected patients, as well as on histological examination of affected tissue showing arterial thrombi [12, 13]. Initial symptoms in most cases included pain and swelling with eventual gangrene formation if left untreated. Digital ischemia and gangrene can be part of the initial presentation of GPA or develop later in the course of the disease, even while the patient is on active treatment. The diagnosis is usually made based on clinical grounds, but angiographic examination can support vasculitic or thrombotic lesions [7- 20]. Pathology can demonstrate either vascular arteritis or thrombi formation [9, 12, 13, 15]. There is no consensus on treatment regarding GPA with digital vasculitis with ischemia and gangrene. However, cyclophosphamide and steroids are the most commonly used treatment in the literature [7-20]. Other therapies that have been used include anticoagulation and vasodilators. Surgical intervention with thrombectomy and bypass have been used as well.
Digital ischemia and gangrene are rare manifestations of GPA. They can have a heterogeneous presentation as demonstrated by the cases in the literature. Diagnosis can be difficult as biopsy of the skin is often nonspecific. Without treatment, ischemia and gangrene can progress and lead to significant disability. Therefore, it is important for clinicians to be aware of this rare manifestation and institute early treatment as indicated.
The authors declare that there is no conflict of interests regarding the publication of this paper.
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Richard A. Lau, (1) Ramandeep Bains, (1) Duminda Suraweera, (2) Jane Ma, (2) Emil R. Heinze, (1,2) Andrew L. Wong, (1,2) and Philip J. Clements (1)
(1) UCLA-Olive View Rheumatology Program, Division of Rheumatology, Olive View-UCLA Medical Center, 14445 Olive View Drive, 2B182, Sylmar, CA 91342, USA
(2) UCLA-Olive View Internal Medicine Program, Department of Medicine, Olive View-UCLA Medical Center, 14445 Olive View Drive, 2B182, Sylmar, CA 91342, USA
Correspondence should be addressed to Emil R. Heinze; firstname.lastname@example.org
Received 22 August 2016; Revised 19 October 2016; Accepted 24 January 2017; Published 28 February 2017
Academic Editor: Shigeko Inokuma
Caption: Figure 1
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Table 1: Literature review of digital ischemia and gangrene associated with GPA in adults. Onset after Age/ initial GPA sex symptoms cANCA Biopsy status 30/M 3-4 months Positive Skin: nonspecific chronic inflammation Renal: segmental necrotizing GN 80/M 1-2 years Positive Skin: leukocytoclastic vasculitis 68/M 2 years Not available Sural nerve: vasculitis with secondary demyelination Lung: nodular necrotizing granulomatous inflammation with vasculitis 26/F 1-2 years Positive Renal: focal crescentic GN Nasopharyngeal: small artery vasculitis 48/M 3 months Positive Renal: pauci immune GN 24/F On presentation Positive Femoral artery: normal 55/M 3-4 months Negative Nasopharyngeal: epithelial ulceration with vasculitis 58/M Unclear Not available Renal: 30% crescents 40/M Unclear Not available Renal: granuloma and vasculitis with 30% crescents Respiratory tract: vasculitis 39/F On presentation Positive Lung: patchy nodular fibrotic changes with hemosiderin laden macrophages and diffuse alveolar hemorrhage Left 4th gangrene digit: vasculitic changes with no thrombotic phenomenon 45/M 2 years Positive Renal: necrotizing GN 41/M 2 years Positive Sinus: granulomatous vasculitis 49/M On presentation Positive Sural nerve: axonal loss 61/F 4 months Positive Renal: focal segmental necrotizing GN 46/F 2 months Positive Skin: leukocytoclastic vasculitis 26/M On presentation Positive Skin: superficial dermal blood vessel necrosis 62/M On presentation Positive Age/ sex Other organ systems involved Management 30/M Sinusitis, epistaxis, Cyclophosphamide and arthralgias, painless oral steroids ulcers, active urine sediment, mild renal insufficiency (creat. 2.3 mg/dL), and left upper lung lobe fibrotic infiltrates 80/M Multiple lung opacities with Cyclophosphamide and incomplete cavitation, renal steroids insufficiency (creat. 1.5 mg/ dL), microscopic hematuria, sensorineural hearing loss, and nasal ulcers 68/M Purulent sinusitis, renal Cyclophosphamide and insufficiency (creat. 1.7 mg/ steroids dL), right peroneal neuropathy, otitis media, right 7th nerve palsy, pulmonary nodules, left pleural effusion, and pyoderma gangrenosum 26/F Secretory otitis, Not specified conjunctivitis, tonsillitis, arthritis, hematuria, mild renal insufficiency, mucosal ulcerations, and palpable purpura 48/M Acute kidney injury (creat. 4.6 Cyclophosphamide, mg/dL), nasal crusting, steroids, heparin, hemoptysis, right sided aspirin, calcium channel pleuritic chest pain, and active blockers, nitroglycerin urine sediment ointment, and plasmapheresis 24/F Pulmonary infiltrates, splenic Cyclophosphamide, infarcts, hemoptysis, and steroids, heparin, and nodular masses in bilateral thrombectomy lungs with diffuse interstitial lung disease 55/M Epistaxis, polyarthralgia, Cyclophosphamide, bilateral lung nodular densities steroids, warfarin, with cavitations, and small thrombectomy, and bypass pleural effusion 58/M ENT, sinusitis, bronchiectasis, Immunosuppression (not lung infiltrates, renal specified) insufficiency (creat. 4.7 mg/ dL), eye, and joint pain 40/M ENT, lung infiltrates, renal Immunosuppression (not failure requiring hemodialysis specified) (creat. 18.43 mg/dL), joint pain, eye, vasculitic skin rash, and mononeuritis multiplex 39/F Hemoptysis, decline in Cyclophosphamide, respiratory function, and steroids, and bilateral pulmonary infiltrates plasmapheresis 45/M Polyneuropathy, renal injury, Cyclophosphamide, arthralgia, mild bloody nasal steroids, heparin, discharge, and skin vasculitis aspirin, and iloprost 41/M Bloody nasal discharge, inner Cyclophosphamide, ear granuloma, polyneuropathy, steroids, heparin, pulmonary infiltrates, and aspirin, and iloprost destructive sinusitis 49/M Mononeuritis multiplex with left Cyclophosphamide, foot drop, and cavitary nodule steroids in the lung 61/F Joint pain, Raynaud's, and acute Cyclophosphamide, kidney injury steroids 46/F Polyarthralgias, epistaxis, Cyclophosphamide, sinusitis, mouth ulcers, steroids, and iloprost episcleritis, mononeuritis multiplex, multiple nodules in right lung, and active urine sediment 26/M Oligoarthritis, polydipsia, Cyclophosphamide, polyuria, lung nodules, and steroids, and mucosal thickening of maxillary azathioprine sinus 62/M Nasal ulceration and congestion, Cyclophosphamide, epistaxis, episcleritis, steroids hemoptysis, diffuse alveolar hemorrhage, pulmonary infiltrates, joint pain, renal insufficiency (creat. 1.7), and active urine sediment Age/ sex Outcome Reference 30/M Gangrene formation with Handa and Wali  autoamputation 80/M Gangrene formation, La Civita et al.  improvement of reversible tissue ischemia 68/M Gangrene formation with Phillips and Twiest  surgical debridement and amputation 26/F Gangrene formation Karjalainen and Hakala  48/M Gangrene formation with Lim et al.  autoamputation 24/F Gangrene formation with Bessias et al.  surgical amputation 55/M Improvement of reversible Maia et al.  tissue ischemia 58/M Gangrene formation Pinching et al.  40/M Gangrene formation Pinching et al.  39/F Gangrene formation with Leung et al.  surgical amputation, improvement of reversible tissue ischemia 45/M Improvement of reversible Schmidt et al.  tissue ischemia 41/M Improvement of reversible Schmidt et al.  tissue ischemia 49/M Acroosteolysis, improvement of Modietal.  reversible ischemia 61/F Gangrene formation with Bartsch et al.  autoamputation 46/F Gangrene formation Kejriwal et al.  26/M Gangrene formation with Agarwal and Khan  autoamputation 62/M Improvement of reversible Current case ischemia, gangrene formation with autoamputation M: male; F: female; ENT: ear, nose, and throat; GN: glomerulonephritis; IV: intravenous.
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|Title Annotation:||Case Report; antineutrophil cytoplasmic antibody|
|Author:||Lau, Richard A.; Bains, Ramandeep; Suraweera, Duminda; Ma, Jane; Heinze, Emil R.; Wong, Andrew L.; C|
|Publication:||Case Reports in Rheumatology|
|Article Type:||Clinical report|
|Date:||Jan 1, 2017|
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