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Atypical ANCA Associated Vasculitis with Rheumatoid Arthritis Overlap

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Atypical ANCA Associated Vasculitis with Rheumatoid Arthritis Overlap Atypical ANCA Associated Vasculitis with Rheumatoid Arthritis Overlap and Literature Review Andrew Jensen, DO, Ali Zaidi, DO, Stanley Skopit, DO, MSE, FAOCD, FAAD Larkin Community Hospital, Department of Dermatology BACKGROUND ANTI-NEUTROPHIL CYTOPLASMIC ANTIBIOTICS (ANCA) OTHER ANCA ASSOCIATIONS Our understanding of the vast world of vasculitis has dramatically improved over the past several Antineutrophil cytoplasmic antibodies or ANCA, describe a well-known immunologic constituent often targeted toward intracellular or ANCA levels may be elevated in many inflammatory conditions including inflammatory bowel disease, decades. However, despite the tremendous progress, anti-neutrophil cytoplasmic autoantibody other molecules that can have detrimental pathophysiological outcomes. C-ANCA or cytoplasmic antineutrophil cytoplasmic antibodies systemic lupus erythematosus, Sjogren’s syndrome, rheumatoid arthritis, reactive arthritis, (ANCA)-associated vasculitides (AAV) is one group of unique immune-mediated vascular diseases typically involves autoantibodies targeting antigens within the cytoplasm of neutrophils with proteinase 3 (PR3) being the suspected antiphospholipid syndrome, polymyositis, anti-glomerular basement membrane disease, autoimmune where diagnostic strategies can pose a challenge. As true for most autoimmune disease states, target. P-ANCA or perinuclear anti neutrophil cytoplasmic antibodies consist of autoantibodies targeting the protein myeloperoxidase hepatitis, primary sclerosing cholangitis, and various infections.15-19 Positive ANCA levels have also general serologic and clinical findings do not always adhere to predictable and reproducible (MPO) also within neutrophils. Detection of ANCA involves indirect immunofluorescence (IIF) of autoantibodies towards these specific been seen in patients that either have rheumatoid factor positive serology, or an actual rheumatoid outcomes, making it difficult for specialists to diagnose and subsequently manage. We present a antigens. Diffuse cytoplasmic staining or perinuclear staining correlate with C-ANCA and P-ANCA respectively. An alternative method for arthritis (RA) diagnosis.20 Typically, ANCA positivity displays years after the diagnosis of RA. Douglas case report of an atypical presentation of cutaneous vasculitis with abnormal ANCA and other screening ANCA is through the use of enzyme-linked immunosorbent assay (ELISA) to detect the specific antibodies targeting either the et al20 studied a subset of patients with positive C-ANCA a diagnosis of RA. They reported two out of serologies, and discuss other diagnostic strategies to consider when presented with atypical ANCA antigen MPO or PR3. Current guidelines recommend completing both the IIF and the ELISA for screening ANCA.9 six patients studied with positive C-ANCA and antibodies to PR3, also had positive rheumatoid factor associated vasculitis. serology. All six patients had rheumatoid arthritis and five of six patients had granulomatous vasculitis There is significant variation in the reported sensitivities and specificities in both detection methods seen in the literature. Classification of seen on biopsy being most consistent with GPA. In each patient, the manifestations of RA were seen the ANCA pattern on IIF is based on objective visual inspection, and depends partly on the examiner's skill, experience and previous prior to GPA with a length of time between the diagnosis of RA and GPA ranging from 8 months to 19 training. There are also no standardized reference ranges and cut off markers for positive and negative titers that vary among different years (mean of 7.9 +- 9.1 years). One retrospective study included six patients who were diagnosed laboratories. The ELISA testing suffers from similar pitfalls as there are also varying cutoff markers and different types of ELISA testing with RA and later developed AAV.2 One patient developed GPA and the other five developed MPA. Half methods which may prove inconsistent when comparing one laboratory to the next. It is, therefore, not surprising to read of significant of the patients had seropositive RA and only half had ANCA positivity, all being MPO-ANCA. The PATIENT PRESENTATION variation of the reported sensitivities and specificities of both testing methods in the literature. median time between the diagnosis of RA and AAV was 10.5 years (range 4-43 years). In a large cross-sectional study of 856 patients, it was demonstrated that the IIF had greater sensitivity than the ELISA.11 However, the Furthermore, Draibe et al. analyzed a total of 29 case reports with association of RA and AAV. Nineteen A 76 year-old female presented to our dermatology office complaining of a rash on her lower ELISA had greater specificity and almost double the positive predictive value for AAV. The sensitivity of ANCA based on IF was 67% and of the patients had renal impairment, four of which had GPA and 15 with MPA.2 Seven of the subjects extremities for several months. She stated the rash was mildly itchy with persistent color changes of the specificity was 93% for AAV, while the sensitivity of ANCA based on ELISA was only 55%, but the specificity was 99%. The were either C-ANCA or PR3-ANCA positive, 11 were P-ANCA or MPO-ANCA positive, seven were red to brown. Her past medical history consisted of atrial fibrillation for which she was taking warfarin combination of a positive IIF and ELISA lead to a much greater likelihood ratio than either test alone which illustrates the importance of ANCA negative, 26 were RF positive, and 10 had a positive ANA. Consensus on the exact etiology of and atenolol. Review of systems was positive for small joint pain and stiffness in the hands and using the combination of the two tests together for diagnostic purposes. the association of RA and AAV has not currently been defined. PTPN22 has been suggested to play a wrists which the patient states were chronic. On physical exam she displayed generalized non- role in the development of RA and certain AAV.21-23 It also worth mentioning again that numerous blanching red to brown palpable purpura on bilateral lower extremities. The patient also showed mild medications have been linked to the development of ANCA associated vasculitis such TNF antagonists ulnar deviation of digits on both hands. FIGURE 1 and penicillamine. Five cases reported by Draibe et al. were reported to be on at least one of these medications and before developing the positive ANCA.2 Two 4mm punch biopsies were collected on the lower legs and the patient was given topical steroids Chart 2: Correlation Between Psoriasis and Comorbidities for symptomatic relief. Laboratory studies were collected (Figure 1). Biopsy results showed an unremarkable epidermis with underlying dermal mononuclear inflammatory infiltrate around the superficial vascular plexus. After pathological and serological review, the patient was diagnosed with an atypical ANCA-associated vasculitis with rheumatoid arthritis overlap. She was started on prednisone 40mg daily with vitamin D and calcium supplementation. She was also given colchicine 0.6mg twice daily and referred to rheumatology. BIBLIOGRAPHY 1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis & Rheumatism. 2012;65(1):1-11. ANCA-ASSOCIATED VASCULITIS (AAV) 2. Draibe J, Salama AD. Association of ANCA associated vasculitis and rheumatoid arthritis: a lesser recognized overlap syndrome. SpringerPlus. 2015;4(1). 3. D'cruz D, Chesser A, Lightowler C, et al. Antineutrophil Cytoplasmic Antibody-Positive Crescentic Glomerulonephritis Associated With Anti-Thyroid Drug Treatment. Rheumatology. 1995;34(11):1090-1091. 4. Gaffey CM, Chun B, Harvey JC, Manz HJ. Phenytoin-induced systemic granulomatous vasculitis. Arch Pathol Lab Med. 1986;110(2):131–135 (Feb) FIGURE 2 5. Ashok D, Dubey S, Tomlinson I. C-ANCA positive systemic vasculitis in a patient with rheumatoid arthritis treated with infliximab. Clinical Rheumatology. Vasculitis is a common condition involving inflammation of vessel walls which can lead to a 2007;27(2):261-264. 6. Noh JY, Asari T, Hamada N, et al. Frequency of appearance of MPO-ANCA in Graves’ disease patients treated with propylthiouracil and the relationship between MPO- disruption of blood supply via either ischemic or hemorrhagic pathways. Any blood vessel may be ANCA and clinical manifestations. Clin Endocrinol 2001; 54:651–654. affected including arteries, arterioles, veins, venules, and capillaries (see figure 2). Vasculitis can 7. Jarrett SJ, Cunnane G, Conaghan PG, Bingham SJ, Buch MH, Quinn MA, Emery P. Anti-tumour necrosis factor-α therapy induced vasculitis. J Rheumatol. 2003;30:102287–102292 generally be classified as either primary, in which the cause of the vascular inflammation is 8. Eriksson C, Engstrand S, Sundqvist K-G, Rantapaa-Dahlqvist S. Autoantibody formation in patients with rheumatoid arthritis treated with anti-TNFα. Ann Rheum Dis. idiopathic, or secondary in which the inflammation can be incited by other inflammatory autoimmune 2005; 64:403–407 9. Savige J, Gilles D, Benson E, et al. International consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies (ANCA). Am J Clin Path 1999; conditions, medications, infections or malignancies. The International Chapel Hill Consensus 111:507–513. Conference (CHCC) has established a nomenclature for noninfectious vasculitides.1 One broad 10. Schulte-Pelkum J, Radice A, Norman GL, et al. Novel Clinical and Diagnostic
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