Laboratory Testing in Neurorheumatology

Abstract

Laboratory testing in cases of neuro-rheumatologic disease can be daunting, and the results can be difficult to interpret if not placed in the correct clinical context. To best help our patients and also to practice in a cost-effective environment, laboratory testing must be performed in a logical manner, guided by symptoms and clinical judgment. The authors discuss the different laboratory tests used in the diagnosis and evaluation of rheumatologic diseases often encountered in the practice of neurology. It is important to understand how the tests are performed and which methods are used at your own institution. Testing should be ordered with a specific diagnosis in mind so as not to confuse the clinical picture with possible false-positive results. Through discussion of the various testing options, the authors advocate a step-wise approach to investigation.

Keywords

antinuclear antibodies - extractable nuclear antigen - rheumatoid factor - erythrocyte sedimentation rate - C-Reactive protein anti-SSA - anti-SSB - cryoglobulins - antineutrophilic cytoplasmic antibody - HLA-B51

• References

• 1 Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111 (12) 1805-1812
• 2 Morley JJ, Kushner I. Serum C-reactive protein levels in disease. Ann N Y Acad Sci 1982; 389: 406-418
• 3 Vercoutere W, Thevissen K, Bombardier C, Landewé RB. Diagnostic and predictive value of acute-phase reactants in adult undifferentiated peripheral inflammatory arthritis: a systematic review. J Rheumatol Suppl 2011; 87: 15-19
• 4 Cantini F, Salvarani C, Olivieri I. Erythrocyte sedimentation rate and C-reactive protein in the diagnosis of polymyalgia rheumatica. Ann Intern Med 1998; 128 (10) 873-874
• 5 Dasgupta B, Cimmino MA, Kremers HM , et al. 2012 Provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Arthritis Rheum 2012; 64 (4) 943-954
• 6 Hunder GG, Bloch DA, Michel BA , et al. The American College of Rheumatology 1990 criteria for the classification of giant cell arteritis. Arthritis Rheum 1990; 33 (8) 1122-1128
• 7 Wong RL, Korn JH. Temporal arteritis without an elevated erythrocyte sedimentation rate. Case report and review of the literature. Am J Med 1986; 80 (5) 959-964
• 8 Laria A, Zoli A, Bocci M, Castri F, Federico F, Ferraccioli GF. Systematic review of the literature and a case report informing biopsy-proven giant cell arteritis (GCA) with normal C-reactive protein. Clin Rheumatol 2012; 31 (9) 1389-1393
• 9 Lopez-Diaz MJ, Llorca J, Gonzalez-Juanatey C, Peña-Sagredo JL, Martin J, Gonzalez-Gay MA. The erythrocyte sedimentation rate is associated with the development of visual complications in biopsy-proven giant cell arteritis. Semin Arthritis Rheum 2008; 38 (2) 116-123
• 10 Farng E, Friedrich JB. Laboratory diagnosis of rheumatoid arthritis. J Hand Surg Am 2011; 36 (5) 926-927 , quiz 928
• 11 Nishimura K, Sugiyama D, Kogata Y , et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med 2007; 146 (11) 797-808
• 12 Shmerling RH, Delbanco TL. The rheumatoid factor: an analysis of clinical utility. Am J Med 1991; 91 (5) 528-534
• 13 García-Carrasco M, Ramos-Casals M, Rosas J , et al. Primary Sjögren syndrome: clinical and immunologic disease patterns in a cohort of 400 patients. Medicine (Baltimore) 2002; 81 (4) 270-280
• 14 Newkirk MM. Rheumatoid factors: what do they tell us?. J Rheumatol 2002; 29 (10) 2034-2040
• 15 Arnett FC, Edworthy SM, Bloch DA , et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31 (3) 315-324
• 16 Aletaha D, Neogi T, Silman AJ , et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62 (9) 2569-2581
• 17 Nell VP, Machold KP, Stamm TA , et al. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis 2005; 64 (12) 1731-1736
• 18 Davids MS, Murali MR, Kuter DJ. Serum free light chain analysis. Am J Hematol 2010; 85 (10) 787-790
• 19 Motyckova G, Murali M. Laboratory testing for cryoglobulins. Am J Hematol 2011; 86 (6) 500-502
• 20 Ramos-Casals M, Stone JH, Cid MC, Bosch X. The cryoglobulinaemias. Lancet 2012; 379 (9813) 348-360
• 21 Bhagat M, Sehra ST, Shahane A, Kwan M. Utility of immunologic testing in suspected rheumatologic disease. Curr Allergy Asthma Rep 2014; 14 (1) 405
• 22 Vermeersch P, Bossuyt X. Prevalence and clinical significance of rare antinuclear antibody patterns. Autoimmun Rev 2013; 12 (10) 998-1003
• 23 Hoffman IE, Peene I, Veys EM, De Keyser F. Detection of specific antinuclear reactivities in patients with negative anti-nuclear antibody immunofluorescence screening tests. Clin Chem 2002; 48 (12) 2171-2176
• 24 Volkmann ER, Taylor M, Ben-Artzi A. Using the antinuclear antibody test to diagnose rheumatic diseases: when does a positive test warrant further investigation?. South Med J 2012; 105 (2) 100-104
• 25 Bossuyt X, Luyckx A. Antibodies to extractable nuclear antigens in antinuclear antibody-negative samples. Clin Chem 2005; 51 (12) 2426-2427
• 26 Bizzaro N, Villalta D, Giavarina D, Tozzoli R. Are anti-nucleosome antibodies a better diagnostic marker than anti-dsDNA antibodies for systemic lupus erythematosus? A systematic review and a study of metanalysis. Autoimmun Rev 2012; 12 (2) 97-106
• 27 Nifli AP, Notas G, Mamoulaki M , et al. Comparison of a multiplex, bead-based fluorescent assay and immunofluorescence methods for the detection of ANA and ANCA autoantibodies in human serum. J Immunol Methods 2006; 311 (1-2) 189-197
• 28 Shanmugam VK, Swistowski DR, Saddic N, Wang H, Steen VD. Comparison of indirect immunofluorescence and multiplex antinuclear antibody screening in systemic sclerosis. Clin Rheumatol 2011; 30 (10) 1363-1368
• 29 Dahle C, Skogh T, Aberg AK, Jalal A, Olcén P. Methods of choice for diagnostic antinuclear antibody (ANA) screening: benefit of adding antigen-specific assays to immunofluorescence microscopy. J Autoimmun 2004; 22 (3) 241-248
• 30 Solomon DH, Kavanaugh AJ, Schur PH ; American College of Rheumatology Ad Hoc Committee on Immunologic Testing Guidelines. Evidence-based guidelines for the use of immunologic tests: antinuclear antibody testing. Arthritis Rheum 2002; 47 (4) 434-444
• 31 Myckatyn SO, Russell AS. Outcome of positive antinuclear antibodies in individuals without connective tissue disease. J Rheumatol 2003; 30 (4) 736-739
• 32 Man A, Shojania K, Phoon C , et al. An evaluation of autoimmune antibody testing patterns in a Canadian health region and an evaluation of a laboratory algorithm aimed at reducing unnecessary testing. Clin Rheumatol 2013; 32 (5) 601-608
• 33 Bonaguri C, Melegari A, Ballabio A , et al. Italian multicentre study for application of a diagnostic algorithm in autoantibody testing for autoimmune rheumatic disease: conclusive results. Autoimmun Rev 2011; 11 (1) 1-5
• 34 Tan EM, Feltkamp TE, Smolen JS , et al. Range of antinuclear antibodies in “healthy” individuals. Arthritis Rheum 1997; 40 (9) 1601-1611
• 35 Mariz HA, Sato EI, Barbosa SH, Rodrigues SH, Dellavance A, Andrade LE. Pattern on the antinuclear antibody-HEp-2 test is a critical parameter for discriminating antinuclear antibody-positive healthy individuals and patients with autoimmune rheumatic diseases. Arthritis Rheum 2011; 63 (1) 191-200
• 36 Mahler M, Fritzler MJ. The clinical significance of the dense fine speckled immunofluorescence pattern on HEp-2 cells for the diagnosis of systemic autoimmune diseases. Clin Dev Immunol 2012; 2012: 494356
• 37 Mahler M, Hanly JG, Fritzler MJ. Importance of the dense fine speckled pattern on HEp-2 cells and anti-DFS70 antibodies for the diagnosis of systemic autoimmune diseases. Autoimmun Rev 2012; 11 (9) 642-645
• 38 Self SE. Autoantibody testing for autoimmune disease. Clin Chest Med 2010; 31 (3) 415-422
• 39 Craig WY, Ledue TB. The relationship between antinuclear antibody data and antibodies against extractable nuclear antigens in a large laboratory cohort. Clin Chem Lab Med 2012; 50 (3) 497-502
• 40 Katz U, Zandman-Goddard G. Drug-induced lupus: an update. Autoimmun Rev 2010; 10 (1) 46-50
• 41 Berlin T, Zandman-Goddard G, Blank M , et al. Autoantibodies in nonautoimmune individuals during infections. Ann N Y Acad Sci 2007; 1108: 584-593
• 42 Timurağaoğlu A, Duman A, Ongüt G, Saka O, Karadoğan I. The significance of autoantibodies in non-Hodgkin's lymphoma. Leuk Lymphoma 2000; 40 (1-2) 119-122
• 43 Covini G, von Mühlen CA, Pacchetti S, Colombo M, Chan EK, Tan EM. Diversity of antinuclear antibody responses in hepatocellular carcinoma. J Hepatol 1997; 26 (6) 1255-1265
• 44 Thomas PJ, Kaur JS, Aitcheson CT, Robinson WA, Tan EM. Antinuclear, antinucleolar, and anticytoplasmic antibodies in patients with malignant melanoma. Cancer Res 1983; 43 (3) 1372-1380
• 45 Abeles AM, Abeles M. The clinical utility of a positive antinuclear antibody test result. Am J Med 2013; 126 (4) 342-348
• 46 Fauchais AL, Martel C, Gondran G , et al. Immunological profile in primary Sjögren syndrome: clinical significance, prognosis and long-term evolution to other auto-immune disease. Autoimmun Rev 2010; 9 (9) 595-599
• 47 Fritzler MJ, Pauls JD, Kinsella TD, Bowen TJ. Antinuclear, anticytoplasmic, and anti-Sjogren's syndrome antigen A (SS-A/Ro) antibodies in female blood donors. Clin Immunol Immunopathol 1985; 36 (1) 120-128
• 48 Alexander EL, Arnett FC, Provost TT, Stevens MB. Sjögren's syndrome: association of anti-Ro(SS-A) antibodies with vasculitis, hematologic abnormalities, and serologic hyperreactivity. Ann Intern Med 1983; 98 (2) 155-159
• 49 Migliorini P, Baldini C, Rocchi V, Bombardieri S. Anti-Sm and anti-RNP antibodies. Autoimmunity 2005; 38 (1) 47-54
• 50 Jearn LH, Kim TY. Anti-Sm faces a threat to its reigning position as the marker antibody. Rheumatol Int 2011; 31 (8) 1119-1120
• 51 Ding Y, He J, Guo JP , et al. Gender differences are associated with the clinical features of systemic lupus erythematosus. Chin Med J (Engl) 2012; 125 (14) 2477-2481
• 52 Webb R, Kelly JA, Somers EC , et al. Early disease onset is predicted by a higher genetic risk for lupus and is associated with a more severe phenotype in lupus patients. Ann Rheum Dis 2011; 70 (1) 151-156
• 53 Benito-Garcia E, Schur PH, Lahita R ; American College of Rheumatology Ad Hoc Committee on Immunologic Testing Guidelines. Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-Sm and anti-RNP antibody tests. Arthritis Rheum 2004; 51 (6) 1030-1044
• 54 Mahler M. Sm peptides in differentiation of autoimmune diseases. Adv Clin Chem 2011; 54: 109-128
• 55 Amigues JM, Cantagrel A, Abbal M, Mazieres B ; Autoimmunity Group of the Hospitals of Toulouse. Comparative study of 4 diagnosis criteria sets for mixed connective tissue disease in patients with anti-RNP antibodies. J Rheumatol 1996; 23 (12) 2055-2062
• 56 Stone KB, Oddis CV, Fertig N , et al. Anti-Jo-1 antibody levels correlate with disease activity in idiopathic inflammatory myopathy. Arthritis Rheum 2007; 56 (9) 3125-3131
• 57 Targoff IN. Autoantibodies and their significance in myositis. Curr Rheumatol Rep 2008; 10 (4) 333-340
• 58 Mammen AL. Dermatomyositis and polymyositis: clinical presentation, autoantibodies, and pathogenesis. Ann N Y Acad Sci 2010; 1184: 134-153
• 59 Cohen-Solal J, Diamond B. Lessons from an anti-DNA autoantibody. Mol Immunol 2011; 48 (11) 1328-1331
• 60 Ghirardello A, Villalta D, Morozzi G , et al; Forum Interdisciplinare per la Ricerca sulle Malattie Autoimmuni(FIRMA) study group. Diagnostic accuracy of currently available anti-double-stranded DNA antibody assays. An Italian multicentre study. Clin Exp Rheumatol 2011; 29 (1) 50-56
• 61 Saigal R, Goyal LK, Agrawal A , et al. Anti-nucleosome antibodies in patients with systemic lupus erythematosus: potential utility as a diagnostic tool and disease activity marker and its comparison with anti-dsDNA antibody. J Assoc Physicians India 2013; 61 (6) 372-377
• 62 McCloskey LJ, Christner P, Jacobs-Kosmin D , et al. Myth and reality: practical test system for the measurement of anti-DNA antibodies in the diagnosis of systemic lupus erythematosus (SLE). J Clin Lab Anal 2010; 24 (2) 77-84
• 63 Kavanaugh AF, Solomon DH ; American College of Rheumatology Ad Hoc Committee on Immunologic Testing Guidelines. Guidelines for immunologic laboratory testing in the rheumatic diseases: anti-DNA antibody tests. Arthritis Rheum 2002; 47 (5) 546-555
• 64 Pan N, Amigues I, Lyman S , et al. A surge in anti-dsDNA titer predicts a severe lupus flare within six months. Lupus 2014; 23 (3) 293-298
• 65 Pisetsky DS. Standardization of anti-DNA antibody assays. Immunol Res 2013; 56 (2-3) 420-424
• 66 Li WX, Pan HF, Li LH , et al. Prevalence and clinical significance of 15 autoantibodies in patients with new-onset systemic lupus erythematosus. Ir J Med Sci 2010; 179 (4) 623-627
• 67 Reddy P. Laboratory diagnosis of antiphospholipid syndrome. South Med J 2013; 106 (7) 439-446
• 68 Jennette JC, Falk RJ, Bacon PA , et al. 2012 Revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013; 65 (1) 1-11
• 69 Birck R, Schmitt WH, Kaelsch IA, van der Woude FJ. Serial ANCA determinations for monitoring disease activity in patients with ANCA-associated vasculitis: systematic review. Am J Kidney Dis 2006; 47 (1) 15-23
• 70 Millet A, Pederzoli-Ribeil M, Guillevin L, Witko-Sarsat V, Mouthon L. Antineutrophil cytoplasmic antibody-associated vasculitides: is it time to split up the group?. Ann Rheum Dis 2013; 72 (8) 1273-1279
• 71 Guillevin L, Durand-Gasselin B, Cevallos R , et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum 1999; 42 (3) 421-430
• 72 Guilpain P, Servettaz A, Goulvestre C , et al. Pathogenic effects of antimyeloperoxidase antibodies in patients with microscopic polyangiitis. Arthritis Rheum 2007; 56 (7) 2455-2463
• 73 Geis C, Weishaupt A, Hallermann S , et al. Stiff person syndrome-associated autoantibodies to amphiphysin mediate reduced GABAergic inhibition. Brain 2010; 133 (11) 3166-3180
• 74 Poh MQ, Simon NG, Buckland ME, Salisbury E, Watson S. Evidence of T-cell mediated neuronal injury in stiff-person syndrome with anti-amphiphysin antibodies. J Neurol Sci 2014; 337 (1-2) 235-237
• 75 de Menthon M, Lavalley MP, Maldini C, Guillevin L, Mahr A. HLA-B51/B5 and the risk of Behçet's disease: a systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum 2009; 61 (10) 1287-1296
• 76 Maldini C, Lavalley MP, Cheminant M, de Menthon M, Mahr A. Relationships of HLA-B51 or B5 genotype with Behcet's disease clinical characteristics: systematic review and meta-analyses of observational studies. Rheumatology (Oxford) 2012; 51 (5) 887-900