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Ohta Y, Tsuchiya T, Oka M, Tachibana M, Kondo Y, Fukushima K, Matsuno S, Yamanaka N, Suzuki N, Komatsu A, Rokutan H, Yumura W, Arai T, Ishigami A, Itabashi M, Takei T. Successful treatment with bortezomib for refractory cryoglobulinemic vasculitis triggered by ischemic non-obstructive coronary artery disease. CEN Case Rep 2025:10.1007/s13730-024-00963-2. [PMID: 39760978 DOI: 10.1007/s13730-024-00963-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 12/16/2024] [Indexed: 01/07/2025] Open
Abstract
Type I and mixed cryoglobulinemic vasculitis differ in pathophysiology, clinical presentation, and therapeutic response. We report a case of refractory cryoglobulinemic vasculitis diagnosed following ischemic non-obstructive coronary artery disease (INOCA). The patient presented with dyspnea, as well as abdominal pain due to ischemic enteritis, purpura, and renal failure requiring dialysis. Despite the patient's IgG λ-type monoclonal gammopathy of undetermined significance (MGUS) and negative hepatitis C virus, the presence of rheumatoid factor (RF) activity and the possibility of IgM involvement were suggested by cryoglobulin analysis and strong glomerular IgM deposition. The condition was diagnosed as mixed cryoglobulinemia, and various immunomodulatory treatments, including methylprednisolone, rituximab and plasmapheresis, were administered without achieving cryoglobulin negativity. However, treatment with bortezomib and dexamethasone ultimately led to cryoglobulin negativity and clinical improvement although the patient was not weaned off dialysis, resulting in remission of the cryoglobulinemic vasculitis. This case suggests that bortezomib, a proteasome inhibitor, may be a promising treatment for refractory cryoglobulinemic vasculitis.
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Affiliation(s)
- Yui Ohta
- Department of Nephrology and Dialysis, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Takaaki Tsuchiya
- Department of Nephrology and Dialysis, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Masatoshi Oka
- Department of Nephrology and Dialysis, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Moriaki Tachibana
- Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Yoshitaka Kondo
- Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Kaoruko Fukushima
- Department of Nephrology and Dialysis, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Shiho Matsuno
- Department of Nephrology and Dialysis, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Noriko Yamanaka
- Department of Nephrology and Dialysis, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Noriyuki Suzuki
- Department of Nephrology and Dialysis, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Akiko Komatsu
- Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Hirofumi Rokutan
- Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Wako Yumura
- Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University Hospital, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Tomio Arai
- Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Akihito Ishigami
- Molecular Regulation of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Mitsuyo Itabashi
- Department of Nephrology and Dialysis, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan
| | - Takashi Takei
- Department of Nephrology and Dialysis, Tokyo Metropolitan Institute for Geriatrics and Gerontology, 35-2 Sakae-Cho, Itabashi, Tokyo, 173-0015, Japan.
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Touiti S, Serroukh S, Benyass A, Bouattar T. Myopericarditis in a Patient With Cryoglobulinemic Kidney Disease: A Case Report. Cureus 2024; 16:e75550. [PMID: 39803028 PMCID: PMC11723568 DOI: 10.7759/cureus.75550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2024] [Indexed: 01/16/2025] Open
Abstract
Cryoglobulinemic vasculitis is a rare small-vessel vasculitis leading to multi-organ dysfunction, often associated with chronic infections like hepatitis C virus (HCV), and autoimmune disorders. Most cases involve mixed monoclonal or polyclonal immunoglobulins, presenting symptoms such as purpura, arthralgias, and weakness. Severe organ involvement, particularly cardiac, is rare but potentially life-threatening. We report the case of a 48-year-old woman without prior medical history who presented with acute dyspnea, generalized petechial purpura, and signs of global heart failure. Imaging and laboratory findings indicated cardiomegaly, pericardial effusion, and significant nephrotic syndrome with renal failure. The diagnosis of cryoglobulinaemia was confirmed through histology and serology, showing monoclonal IgM with kappa hypergammaglobulinaemia and complement consumption. Treatment included various immunosuppressants, corticosteroids, and rituximab combined with renal replacement therapy. Following the initiation of treatment and proper management of heart failure, the patient's condition significantly improved. Cardiac involvement in cryoglobulinemic vasculitis, though rare, can lead to severe heart failure. This often involves necrotizing vasculitis of the coronary arteries or systemic inflammation damaging the cardiac muscle, as observed here. Cardiac manifestations with immunosuppressive therapy are reversible despite a poor long-term prognosis for patients with cardiac lesions. In conclusion, cryoglobulinemic vasculitis has a grim prognosis due to its multi-organ impact and the severity of the lesions. Early and aggressive treatment is essential to manage life-threatening acute presentations, even before confirming the diagnosis biologically or histologically.
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Affiliation(s)
- Soufiane Touiti
- Cardiology, Ibn Sina Hospital, Rabat, Rabat, MAR
- Cardiology, Mohammed V Military Training Hospital, Rabat, MAR
| | | | - Aatif Benyass
- Cardiology, Mohammed V Military Instruction Hospital of Rabat, Mohammed V University, Rabat, MAR
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Spyropoulou M, Montanes‐Sancho I, Gow AG, Bussey S. Cryoglobulinemia Associated With Multiple Myeloma in a Dog Presenting With Epistaxis and Skin Lesions. Vet Med Sci 2024; 10:e70084. [PMID: 39427324 PMCID: PMC11491071 DOI: 10.1002/vms3.70084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 08/28/2024] [Accepted: 09/30/2024] [Indexed: 10/22/2024] Open
Abstract
A 10-year-old female neutered Labrador Retriever presented with epistaxis, discoloration and crusting of the nose and a necrotic lesion on the lip. Bloodwork revealed pancytopenia, azotemia, hypoalbuminemia and hyperglobulinemia. Aggregates of amorphous basophilic material were seen in a room-temperature blood smear which were not present in the sample after warming to 37°C, and grossly a cryoprecipitate was noted in the patient's serum at 4°C. This was interpreted as cryoglobulin. Computed tomography showed multiple heterogeneous lesions in the spleen. Cytology of the splenic lesions revealed marked plasma cell infiltration, consistent with neoplasia. Bone marrow aspiration revealed an increased proportion of plasma cells (approximately 38% of the total cells). Serum protein electrophoresis showed a monoclonal spike in the gamma globulin region. A diagnosis of multiple myeloma associated with cryoglobulinemia was made. The patient received palliative care with prednisolone while the owner was considering chemotherapy. However, she rapidly deteriorated and was euthanized. The combination of cryoglobulin precipitation and hyperviscosity syndrome was considered responsible for the patient's original symptoms. Cryoglobulinemia is an extremely rare phenomenon that is often associated with lymphoproliferative disorders. This report describes its association with multiple myeloma in a dog presenting with atypical initial signs.
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Affiliation(s)
- Myrto Spyropoulou
- Easter Bush PathologyThe Royal (Dick) School of Veterinary Studies and The Roslin Institute, University of EdinburghEdinburghUK
| | - Ivan Montanes‐Sancho
- Hospital for Small AnimalsThe Royal (Dick) School of Veterinary Studies and The Roslin Institute, University of EdinburghEdinburghUK
| | - Adam G. Gow
- Hospital for Small AnimalsThe Royal (Dick) School of Veterinary Studies and The Roslin Institute, University of EdinburghEdinburghUK
| | - Suzanne Bussey
- Easter Bush PathologyThe Royal (Dick) School of Veterinary Studies and The Roslin Institute, University of EdinburghEdinburghUK
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Codes-Méndez H, Jeria S, Park HS, Moya P, Magallares-López B, Moltó E, Álvaro Y, Mariscal A, Moga E, Tandaipan JL, Díaz-Torne C, Laiz A, Sainz L, Castellví I, Corominas H. Clinical and Serological Profiles in Cryoglobulinemia: Analysis of Isotypes and Etiologies. J Clin Med 2024; 13:6069. [PMID: 39458019 PMCID: PMC11508573 DOI: 10.3390/jcm13206069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 10/02/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Objectives: Cryoglobulinemia (CG) is marked by abnormal immunoglobulins (Ig) in serum, precipitating at temperatures below 37 °C. Current classification categorizes CG into three subtypes (types I, II, and III) based on Ig clonality. The features distinguishing patients with CG based on their etiology remain unidentified. Aiming to characterize clinical and serological profiles of CG individuals, we conducted an observational analysis of a large cohort of patients and compared their characteristics based on underlying causes: hepatovirus (HV) infections, rheumatic diseases (RD), hematological disorders, and unidentified etiology (essential CG). Methods: We analyzed 252 cryoglobulin-positive serum samples from 182 patients and classified these into the four etiological groups. A separate sub-analysis was carried out for 10 patients meeting criteria for multiple diseases. We collected demographic, clinical, and laboratory data: CG characterization, complement (C3 and C4) levels, antinuclear antibodies (ANA), and rheumatoid factor (RF). Kruskal-Wallis and Wilcoxon-Mann-Whitney U-tests were used for comparisons. Results: Most patients (93.3%) had mixed cryoglobulinemia (types II + III), with 6.7% having type I. HV infection, predominantly hepatitis C, was the main (52.9%) associated condition within the cohort, followed by rheumatic (27.3%) and hematological (9.8%) disorders. In our cohort, ANA were frequent (45.3%) and often associated with RF positivity (43.6%) and decreased complement levels (C3: 42.4%, C4: 32.5%). Essential CG and CG associated with RD had a higher prevalence of cutaneous manifestations (p < 0.01) and renal involvement (p = 0.017). Hematological disorder-related CG showed higher cryoglobulin and RF concentrations (p < 0.01), despite milder symptoms. Conclusions: Our study underscores a mixed prevalence of CG across disease subgroups, with hepatitis-C virus as the primary factor, followed by rheumatic and hematological disorders. Four clinical and serological profiles of CG were identified based on their etiologies.
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Affiliation(s)
- Helena Codes-Méndez
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (H.C.-M.); (S.J.); (H.-S.P.); (P.M.); (B.M.-L.); (J.L.T.); (C.D.-T.); (A.L.); (L.S.); (I.C.)
| | - Sicylle Jeria
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (H.C.-M.); (S.J.); (H.-S.P.); (P.M.); (B.M.-L.); (J.L.T.); (C.D.-T.); (A.L.); (L.S.); (I.C.)
| | - Hye-Sang Park
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (H.C.-M.); (S.J.); (H.-S.P.); (P.M.); (B.M.-L.); (J.L.T.); (C.D.-T.); (A.L.); (L.S.); (I.C.)
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
- Multi-Organ Damage and Rheumatology Group, Sant Pau Biomedical Research Institute (IIB Sant Pau), 08025 Barcelona, Spain
- Medicine Faculty, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
| | - Patricia Moya
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (H.C.-M.); (S.J.); (H.-S.P.); (P.M.); (B.M.-L.); (J.L.T.); (C.D.-T.); (A.L.); (L.S.); (I.C.)
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
- Multi-Organ Damage and Rheumatology Group, Sant Pau Biomedical Research Institute (IIB Sant Pau), 08025 Barcelona, Spain
- Medicine Faculty, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
| | - Berta Magallares-López
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (H.C.-M.); (S.J.); (H.-S.P.); (P.M.); (B.M.-L.); (J.L.T.); (C.D.-T.); (A.L.); (L.S.); (I.C.)
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
- Multi-Organ Damage and Rheumatology Group, Sant Pau Biomedical Research Institute (IIB Sant Pau), 08025 Barcelona, Spain
- Medicine Faculty, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
| | - Elisabeth Moltó
- Immunology Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (E.M.); (Y.Á.); (A.M.); (E.M.)
| | - Yolanda Álvaro
- Immunology Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (E.M.); (Y.Á.); (A.M.); (E.M.)
| | - Anais Mariscal
- Immunology Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (E.M.); (Y.Á.); (A.M.); (E.M.)
| | - Esther Moga
- Immunology Department, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (E.M.); (Y.Á.); (A.M.); (E.M.)
| | - Jose Luis Tandaipan
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (H.C.-M.); (S.J.); (H.-S.P.); (P.M.); (B.M.-L.); (J.L.T.); (C.D.-T.); (A.L.); (L.S.); (I.C.)
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
- Multi-Organ Damage and Rheumatology Group, Sant Pau Biomedical Research Institute (IIB Sant Pau), 08025 Barcelona, Spain
- Medicine Faculty, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
| | - César Díaz-Torne
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (H.C.-M.); (S.J.); (H.-S.P.); (P.M.); (B.M.-L.); (J.L.T.); (C.D.-T.); (A.L.); (L.S.); (I.C.)
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
- Multi-Organ Damage and Rheumatology Group, Sant Pau Biomedical Research Institute (IIB Sant Pau), 08025 Barcelona, Spain
- Medicine Faculty, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
| | - Ana Laiz
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (H.C.-M.); (S.J.); (H.-S.P.); (P.M.); (B.M.-L.); (J.L.T.); (C.D.-T.); (A.L.); (L.S.); (I.C.)
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
- Multi-Organ Damage and Rheumatology Group, Sant Pau Biomedical Research Institute (IIB Sant Pau), 08025 Barcelona, Spain
- Medicine Faculty, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
| | - Luis Sainz
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (H.C.-M.); (S.J.); (H.-S.P.); (P.M.); (B.M.-L.); (J.L.T.); (C.D.-T.); (A.L.); (L.S.); (I.C.)
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
- Multi-Organ Damage and Rheumatology Group, Sant Pau Biomedical Research Institute (IIB Sant Pau), 08025 Barcelona, Spain
- Medicine Faculty, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
| | - Ivan Castellví
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (H.C.-M.); (S.J.); (H.-S.P.); (P.M.); (B.M.-L.); (J.L.T.); (C.D.-T.); (A.L.); (L.S.); (I.C.)
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
- Multi-Organ Damage and Rheumatology Group, Sant Pau Biomedical Research Institute (IIB Sant Pau), 08025 Barcelona, Spain
- Medicine Faculty, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
| | - Hector Corominas
- Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain; (H.C.-M.); (S.J.); (H.-S.P.); (P.M.); (B.M.-L.); (J.L.T.); (C.D.-T.); (A.L.); (L.S.); (I.C.)
- Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
- Multi-Organ Damage and Rheumatology Group, Sant Pau Biomedical Research Institute (IIB Sant Pau), 08025 Barcelona, Spain
- Medicine Faculty, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
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Patel D, Sargur R, Sheldon J, Wheeler RD, Stanley C. Evaluation of cryoprotein investigation using a digital external quality assurance scheme. Ann Clin Biochem 2024; 61:347-355. [PMID: 38428927 DOI: 10.1177/00045632241239805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/03/2024]
Abstract
Background: Robust preanalytical and analytical processes are critical for the detection of cryoproteins. There is significant variation in practice in the detection, analysis and reporting. Results: A survey in 2018 of 137 laboratories participating in the UK National External Quality Assessment Service (UK NEQAS) (6) quality control program showed significant variation in the laboratory processes which highlighted the need for standardisation of the detection, analysis and reporting of cryoglobulins.Conclusion: The first available EQA scheme aiming to harmonise practice for cryoprotein testing has been developed by UK NEQAS and laboratories should participate in an appropriate EQA scheme to fulfil requirements for ISO accreditation.
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Affiliation(s)
- Dina Patel
- UK NEQAS Immunology, Immunochemistry & Allergy (IIA), Sheffield, UK
| | | | - Joanna Sheldon
- Protein Reference Unit, St George's Hospital, London, UK
| | | | - Carol Stanley
- UK NEQAS Immunology, Immunochemistry & Allergy (IIA), Sheffield, UK
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Anderson H, Rollo C, O'Donnell J. Cryoglobulinaemia sine cryoglobulin: a heat insoluble cryoglobulin. Pathology 2024; 56:734-736. [PMID: 38599960 DOI: 10.1016/j.pathol.2024.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/09/2023] [Accepted: 01/11/2024] [Indexed: 04/12/2024]
Affiliation(s)
- Hamish Anderson
- Department of Immunology, Canterbury Health Laboratories, Christchurch, New Zealand.
| | - Catherine Rollo
- Department of Protein Chemistry and Endocrinology, Canterbury Health Laboratories, Christchurch, New Zealand
| | - John O'Donnell
- Department of Immunology, Canterbury Health Laboratories, Christchurch, New Zealand
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Hortin GL, Stapp RT, Thapa SB, Grajales-Cruz AF. Problematic Proteins: A Patient with a High Paraprotein Concentration. Clin Chem 2024; 70:905-908. [PMID: 38965700 DOI: 10.1093/clinchem/hvae065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 03/25/2024] [Indexed: 07/06/2024]
Affiliation(s)
- Glen L Hortin
- Department of Pathology, Moffitt Cancer Center, Tampa, FL, United States
- Department of Oncologic Science, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Robert T Stapp
- Department of Pathology, Moffitt Cancer Center, Tampa, FL, United States
- Department of Oncologic Science, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Shrinjaya B Thapa
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, United States
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Schrader SM. Commentary on Problematic Proteins: A Case with High Paraprotein Concentration. Clin Chem 2024; 70:909-910. [PMID: 38965699 DOI: 10.1093/clinchem/hvae063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Accepted: 03/27/2024] [Indexed: 07/06/2024]
Affiliation(s)
- Sarah M Schrader
- Department of Pathology, Mass General Brigham, Boston, MA, United States
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9
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Ogrič M, Švec T, Poljšak KM, Lakota K, Podovšovnik E, Kolopp-Sarda MN, Hočevar A, Čučnik S. Insights into the immunological description of cryoglobulins with regard to detection and characterization in Slovenian rheumatological patients. Immunol Res 2024; 72:185-196. [PMID: 37993756 PMCID: PMC11031437 DOI: 10.1007/s12026-023-09434-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 11/06/2023] [Indexed: 11/24/2023]
Abstract
The detection of cryoglobulins (CG) used to diagnose cryoglobulinemic vasculitis requires strict adherence to protocol, with emphasis on the preanalytical part. Our main objectives were to introduce a more sensitive and specific protocol for the detection of CG and to characterize CG in Slovenian patients diagnosed with cryoglobulinemic vasculitis, other vasculitides, connective tissue diseases or non-rheumatic diseases examined at the Department of Rheumatology (University Medical Centre Ljubljana). Samples were routinely analyzed for the presence of CG with the protocol using the Folin-Ciocalteu reagent. In the newly introduced protocol, the type of CG was determined by immunofixation on visually observed positive samples and the concentration of CG in the cryoprecipitate and rheumatoid factor (RF) activity were measured by nephelometry. RF, C3c and C4 were measured in patients` serum and a decision tree analysis was performed using all results. The agreement between negative and positive results between the two protocols was 86%. Of the 258 patient samples tested, we found 56 patients (21.7%) with positive CG (37.5% - type II, 62.5% - type III). The RF activity was observed in 21.4% of CG positive subjects. The median concentration of type II CG was significantly higher than that of type III CG (67.4 mg/L vs. 45.0 mg/L, p = 0.037). Patients with type II had lower C4 concentrations and higher RF compared to patients with type III CG. In the decision tree, C4 was the strongest predictor of cryoglobulinemia in patients. With the newly implemented protocol, we were able to improve the detection and quantification of CG in the samples of our rheumatology patients and report the results to adequately support clinicians.
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Affiliation(s)
- Manca Ogrič
- Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tinka Švec
- Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Katjuša Mrak Poljšak
- Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Katja Lakota
- Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- FAMNIT, University of Primorska, Koper, Slovenia
| | | | - Marie Nathalie Kolopp-Sarda
- Immunogenomics and Inflammation Research, University of Lyon, Lyon, France
- Immunology Laboratory, University Hospital Lyon, Lyon, France
| | - Alojzija Hočevar
- Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Saša Čučnik
- Department of Rheumatology, University Medical Centre Ljubljana, Ljubljana, Slovenia.
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia.
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Khwaja J, Japzon N, Gabriel M, Raju K, Rajaratnam V, Gupta R, Rismani A, Kyriakou C, D'Sa S. Cold agglutinin disease and cryoglobulinaemia: A frequent coexistence with clinical impact. Br J Haematol 2024; 204:e21-e24. [PMID: 37920938 DOI: 10.1111/bjh.19185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 10/15/2023] [Accepted: 10/20/2023] [Indexed: 11/04/2023]
Affiliation(s)
- Jahanzaib Khwaja
- Department of Haematology, University College London Hospital, London, UK
| | - Nicole Japzon
- Department of Haematology, University College London Hospital, London, UK
| | - Maria Gabriel
- Department of Medicine, University College London, London, UK
| | - Kavin Raju
- Department of Medicine, University College London, London, UK
| | | | - Rajeev Gupta
- Department of Haematology, University College London Hospital, London, UK
| | - Ali Rismani
- Department of Haematology, University College London Hospital, London, UK
| | - Chara Kyriakou
- Department of Haematology, University College London Hospital, London, UK
| | - Shirley D'Sa
- Department of Haematology, University College London Hospital, London, UK
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Khwaja J, Vos JMI, Pluimers TE, Japzon N, Patel A, Salter S, Kwakernaak AJ, Gupta R, Rismani A, Kyriakou C, Wechalekar AD, D'Sa S. Clinical and clonal characteristics of monoclonal immunoglobulin M-associated type I cryoglobulinaemia. Br J Haematol 2024; 204:177-185. [PMID: 37726004 DOI: 10.1111/bjh.19112] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/30/2023] [Accepted: 09/07/2023] [Indexed: 09/21/2023]
Abstract
Monoclonal immunoglobulin M-associated type I cryoglobulinaemia is poorly characterised. We screened 534 patients with monoclonal IgM disorders over a 9-year period and identified 134 patients with IgM type I cryoglobulins. Of these, 76% had Waldenström macroglobulinaemia (WM), 5% had other non-Hodgkin lymphoma (NHL) and 19% had IgM monoclonal gammopathy of undetermined significance (MGUS). Clinically relevant IgM-associated disorders (including cold agglutinin disease [CAD], anti-MAG antibodies, amyloidosis and Schnitzler syndrome) coexisted in 31%, more frequently in MGUS versus WM/NHL (72% vs. 22%/29%, p < 0.001). The majority of those with cryoglobulins and coexistent CAD/syndrome had the molecular characteristics of a CAD clone (wild-type MYD88 in 80%). A half of all patients had active manifestations at cryoglobulin detection: vasomotor (22%), cutaneous (16%), peripheral neuropathy (22%) and hyperviscosity (9%). 16/134 required treatment for cryoglobulin-related symptoms alone at a median of 38 days (range: 6-239) from cryoglobulin detection. At a median follow-up of 3 years (range: 0-10), 3-year cryoglobulinaemia-treatment-free survival was 77% (95% CI: 68%-84%). Age was the only predictor of overall survival. Predictors of cryoglobulinaemia-related treatment/death were hyperviscosity (HR: 73.01; 95% CI: 15.62-341.36, p < 0.0001) and cutaneous involvement (HR: 2.95; 95% CI: 1.13-7.71, p = 0.028). Type I IgM cryoglobulinaemia is more prevalent than previously described in IgM gammopathy and should be actively sought.
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Affiliation(s)
- Jahanzaib Khwaja
- Department of Haematology, University College London Hospital, London, UK
| | - Josephine M I Vos
- Department of Haematology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Tessa E Pluimers
- Department of Haematology, Amsterdam UMC, Amsterdam, The Netherlands
| | - Nicole Japzon
- Department of Haematology, University College London Hospital, London, UK
| | - Aisha Patel
- Department of Haematology, University College London Hospital, London, UK
| | | | - Arjan J Kwakernaak
- Department of Internal Medicine, Clinical Immunology/Allergy and Nephrology Amsterdam UMC, Amsterdam, The Netherlands
| | - Rajeev Gupta
- Department of Haematology, University College London Hospital, London, UK
| | - Ali Rismani
- Department of Haematology, University College London Hospital, London, UK
| | | | | | - Shirley D'Sa
- Department of Haematology, University College London Hospital, London, UK
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12
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Chong YP, Lim SM, Loh TP, Mollee P, Wijeratne N, Choy KW. Screening for and diagnosis of monoclonal gammopathy. J Clin Pathol 2023; 76:727-733. [PMID: 37604683 DOI: 10.1136/jcp-2023-208774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/03/2023] [Indexed: 08/23/2023]
Abstract
Monoclonal gammopathy is a spectrum of disorders characterised by clonal proliferation of plasma cells or lymphocytes, which produce abnormal immunoglobulin or its components (monoclonal proteins). Monoclonal gammopathies are often categorised as low-tumour-burden diseases (eg, amyloid light chain (AL) amyloidosis), premalignant disorders (such as monoclonal gammopathy of undetermined significance and smouldering multiple myeloma), and malignancies (eg, multiple myeloma and Waldenström's macroglobulinaemia). Such diversity of concentration and structure makes monoclonal protein a challenging clonal marker. This article provides an overview on initial laboratory testing of monoclonal gammopathy to guide clinicians and laboratory professionals in the selection and interpretation of appropriate investigations.
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Affiliation(s)
- Yuh Ping Chong
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Say Min Lim
- Department of Pathology, Hospital Teluk Intan, Teluk Intan, Malaysia
| | - Tze Ping Loh
- Department of Laboratory Medicine, National University Hospital, Singapore
| | - Peter Mollee
- Pathology Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Nilika Wijeratne
- Dorevitch Pathology, Heidelberg, Victoria, Australia
- School of Clinical Sciences at Monash Health, Department of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia
- Eastern Health Pathology, Eastern Health, Box Hill, Victoria, Australia
| | - Kay Weng Choy
- Department of Pathology, Northern Health, Epping, Victoria, Australia
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13
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Punchoo R. Through the looking crystal: clarifying the pathogenesis and laboratory work-up of cryocrystalglobulinaemia. J Clin Pathol 2023; 76:658. [PMID: 34893519 DOI: 10.1136/jclinpath-2021-207585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 06/08/2021] [Indexed: 11/04/2022]
Affiliation(s)
- Rivak Punchoo
- Chemical Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
- Chemical Pathology, Tshwane Academic Divsion, National Health Laboratory Service, Pretoria, South Africa
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14
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Stoyanov A, Toong C, Kong Y, Chen R, Urriola N. Serum protein electrophoresis and rheumatoid factor analysis is an effective screening strategy for cryoglobulinaemia. Pathology 2023; 55:391-396. [PMID: 36494206 DOI: 10.1016/j.pathol.2022.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 08/05/2022] [Accepted: 09/06/2022] [Indexed: 11/15/2022]
Abstract
Accurate serum cryoglobulin detection is important to allow prompt treatment but laboratory testing requires stringent pre-analytical conditions and has long turnaround times. Serum protein electrophoresis (EPG) for paraproteinaemia and rheumatoid factor (RF) analysis may offer an effective initial screening strategy for the presence of cryoglobulinaemia. We retrospectively assessed the sensitivity of ancillary EPG and RF testing for the presence of serum cryoglobulinaemia in 586 eligible cryoglobulin positive samples received at the Royal Prince Alfred and Liverpool Hospital immunopathology laboratories over an 11-year period. Ninety-one percent of all cryoglobulin positive samples had either a detectable paraprotein or RF activity, with greatest sensitivity for type I and type II cryoglobulins (97% and 98%, respectively). The sensitivity remained high irrespective of whether EPG and RF analysis was performed with the same, or different, pre-analytical collection conditions to the cryoglobulin collection (92% vs 90%, p=0.46). Only two patients with detected cryoglobulins and no associated paraprotein or RF activity had clinical features of cryoglobulinaemia and neither required treatment. This study demonstrates that serum EPG and RF analysis has high sensitivity for the detection of clinically relevant cryoglobulinaemia, even when not collected under ideal pre-analytical conditions, and potentially offers a prompt and effective screening strategy.
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Affiliation(s)
- Alex Stoyanov
- Central Sydney Immunopathology Laboratory, Pathology East, NSW Health Pathology, Sydney, NSW, Australia.
| | - Catherine Toong
- Department of Immunopathology, Liverpool Hospital, NSW Health Pathology, Sydney, NSW, Australia
| | - Yvonne Kong
- Department of Haematology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Renfen Chen
- Central Sydney Immunopathology Laboratory, Pathology East, NSW Health Pathology, Sydney, NSW, Australia
| | - Nicolás Urriola
- Department of Clinical Immunology, Royal Prince Alfred Hospital, Sydney, Australia
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15
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Alsaidi Y, Thompson A, Spilchuk V, House RA, Adisesh A. Cryoglobulins and cold agglutinins for hand arm vibration syndrome. Occup Med (Lond) 2022; 72:609-613. [PMID: 36179074 DOI: 10.1093/occmed/kqac083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Hand arm vibration syndrome (HAVS) is a condition caused by hand transmitted vibration from the use of hand-held vibrating tools or workpieces. The disease affects the vascular, neurological and musculoskeletal systems. The vascular component of HAVS is a form of secondary Raynaud's phenomenon. Other causes of disease must be excluded before attributing the cause to hand transmitted vibration. AIMS To evaluate the prevalence, and utility of testing for, cryoglobulins and cold agglutinins in patients with HAVS symptoms. METHODS A retrospective cohort study of 1183 patients referred for HAVS clinical assessment at St. Michael's Hospital, Toronto, Canada, between 2014 and 2020. The standard operating procedure at the clinic includes a detailed clinical and exposure history, physical examination, objective investigations and blood tests. Data were retrieved from patient chart review and laboratory investigation results for all cases with cryoglobulin and cold agglutinin testing. RESULTS A total of 1183 patients had a serum cryoglobulin measurement. Eleven patients (1%) were positive. Seven positive results were 'low titre' (1% positive) and the other four results were 2%, 6%, 9% and 18%. The patient with a 9% positive cryoglobulin titre had previously diagnosed Sjögren's syndrome. There were no positive cold agglutinin tests in the 795 patients tested. CONCLUSIONS Routine testing for cryoglobulins and cold agglutinins in patients with HAVS symptoms is not recommended because test positivity rates are negligible. Testing may be considered if the clinical history or routine blood investigations suggest evidence of underlying cryoglobulinaemia or cold agglutinin disease.
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Affiliation(s)
- Y Alsaidi
- Division of Occupational Medicine, Department of Medicine, University of Toronto and St. Michael's Hospital, Toronto, Canada
| | - A Thompson
- Division of Occupational Medicine, Department of Medicine, University of Toronto and St. Michael's Hospital, Toronto, Canada
| | - V Spilchuk
- Division of Occupational Medicine, Department of Medicine, University of Toronto and St. Michael's Hospital, Toronto, Canada
| | - R A House
- Division of Occupational Medicine, Department of Medicine, University of Toronto and St. Michael's Hospital, Toronto, Canada
| | - A Adisesh
- Division of Occupational Medicine, Department of Medicine, University of Toronto and St. Michael's Hospital, Toronto, Canada
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16
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Natali P, Debbia D, Cucinelli MR, Trenti T, Amati G, Spinella A, Giuggioli D, Mascia MT, Sandri G. Analysis of cryoproteins with a focus on cryofibrinogen: a study on 103 patients. Clin Chem Lab Med 2022; 60:1796-1803. [PMID: 36082756 DOI: 10.1515/cclm-2022-0423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 08/31/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Cryofibrinogen (CF) is an abnormal protein in plasma that precipitates at 4 °C and dissolves at 37 °C. Whilst serum cryoglobulins (CGs) analysis is common practice, CF investigation is rarely performed. This study aims to describe the testing methodology developed at our laboratory, potential pitfalls for all analytical phases, the distribution among hospital wards and clinical conditions underlying test requests and clinical conditions in which to order CF analysis is useful. METHODS Retrospective analysis of laboratory samples received between January 2019 and June 2021 with CF testing requests. RESULTS A complete protocol for CF pre-analytical, analytical and post-analytical phases are supplied. Most test requests were received from the rheumatology department for systemic sclerosis or liver transplant screening. Among the 103 in-patients included, CF+ was confirmed in 68 patients (66%). Of observed CF+ patients (n=68) most cases were CGs- (n=44, 67%). Isolated CF was found in 43% of the cases. Among CF- patients (n=35; 34%) only 2 patients had positive CGs (CGs+). Among rheumatology patients (n=66), isolated CF+ was observed in 45% (n=30/66), whilst among patients with systemic sclerosis with CF+ (n=19), isolated CF+ was detected in 79% (n=15/19). CONCLUSIONS Described analytical procedures may be used for the creation of harmonized recommendations and indications for CF analysis. Isolated CF positivity among hospitalized patients, predominantly rheumatology and systemic sclerosis patients, appears higher than rates previously reported in literature. We propose CF test recommendations should be included in investigation protocols for diseases where cryofibrinogenemia may occur.
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Affiliation(s)
- Patrizia Natali
- Department of Laboratory Medicine and Pathological Anatomy, Azienda Ospedaliero-Universitaria e Azienda USL di Modena, Modena, Italy
| | - Daria Debbia
- Department of Laboratory Medicine and Pathological Anatomy, Azienda Ospedaliero-Universitaria e Azienda USL di Modena, Modena, Italy
| | - Maria R Cucinelli
- Department of Laboratory Medicine and Pathological Anatomy, Azienda Ospedaliero-Universitaria e Azienda USL di Modena, Modena, Italy
| | - Tommaso Trenti
- Department of Laboratory Medicine and Pathological Anatomy, Azienda Ospedaliero-Universitaria e Azienda USL di Modena, Modena, Italy
| | - Gabriele Amati
- Chair of Rheumatology - Department of Maternal, Child and Adult Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
| | - Amelia Spinella
- Chair of Rheumatology - Department of Maternal, Child and Adult Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
| | - Dilia Giuggioli
- Chair of Rheumatology - Department of Maternal, Child and Adult Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
| | - Maria T Mascia
- Chair of Rheumatology - Department of Maternal, Child and Adult Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
| | - Gilda Sandri
- Chair of Rheumatology - Department of Maternal, Child and Adult Medical and Surgical Sciences, Università degli Studi di Modena e Reggio Emilia, Modena, Italy
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17
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Kolev M, Horn MP, Semmo N, Nagler M. Rational development and application of biomarkers in the field of autoimmunity: A conceptual framework guiding clinicians and researchers. J Transl Autoimmun 2022; 5:100151. [PMID: 35309737 PMCID: PMC8927991 DOI: 10.1016/j.jtauto.2022.100151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/04/2022] [Accepted: 03/05/2022] [Indexed: 11/26/2022] Open
Abstract
Clear guidance is needed in the development and implementation of laboratory biomarkers in medicine. So far, no standardized phased approach is established that would pilot researchers and clinicians in this process. This leads to often incompletely validated biomarkers, which can bear the consequence of wrong applications, misinterpretation and inadequate management in the clinical context. In this conceptual article, we describe a stepwise approach to develop and comprehensively validate laboratory biomarkers. We will delineate basic steps including technical performance, pre-analytical issues, and biological variation, as well as advanced aspects of biomarker utility comprising interpretability, diagnostic and prognostic accuracy, and health-care outcomes. These aspects will be illustrated by using well-known examples from the field of immunology. The application of this conceptual framework will guide researchers in conducting meaningful projects to develop and evaluate biomarkers for the use in clinical practice. Furthermore, clinicians will be able to adequately interpret pre-clinical and clinical diagnostic literature and rationally apply biomarkers in clinical practice. Improvement in the implementation and application of biomarkers might relevantly change the management and outcomes of our patients for the better.
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18
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Kolopp-Sarda MN, Miossec P. Practical Details for the Detection and Interpretation of Cryoglobulins. Clin Chem 2021; 68:282-290. [PMID: 34718470 DOI: 10.1093/clinchem/hvab195] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 08/19/2021] [Indexed: 11/12/2022]
Abstract
BACKGROUND Cryoglobulins are immunoglobulins that precipitate at low temperature. Strict preanalytical and analytical conditions are critical for the detection of cryoglobulins. CONTENT This review will focus on practical recommendations for detection and characterization of cryoglobulins and the technical problems that may be encountered. A laboratory report format is proposed for presentation of these results that includes the parameters necessary for an optimal interpretation by clinicians. The first step of detection of cryoglobulins can be performed in any laboratory that has a 37 °C incubator and temperature-controlled centrifuge. The second step is the characterization of cryoglobulins, and this often must be performed in more specialized laboratories. Characterization includes immunoglobulin typing, for the classification of cryoglobulins and potential underlying disease(s); quantification of immunoglobulins and rheumatoid factor in the cryoprecipitate to define the pathogenicity; and quantification of serum complement, which is useful for diagnosis. SUMMARY These practical recommendations will be useful for the accurate detection of cryoglobulins, an essential step for the diagnosis of cryoglobulinemic vasculitis, a rare but severe clinical manifestation of cryoglobulins.
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Affiliation(s)
- Marie-Nathalie Kolopp-Sarda
- Immunogenomics and Inflammation Research Unit, University of Lyon, Lyon, France.,Immunology Laboratory, Hospices Civils de Lyon, Lyon, France
| | - Pierre Miossec
- Immunogenomics and Inflammation Research Unit, University of Lyon, Lyon, France.,Department of Immunology and Rheumatology, Clinical Immunology Unit, Hospices Civils de Lyon, Lyon, France
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19
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Kolopp-Sarda MN, Miossec P. Key points to consider for an improved detection and characterization of cryoglobulins. Autoimmun Rev 2021; 20:102948. [PMID: 34509653 DOI: 10.1016/j.autrev.2021.102948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 05/02/2021] [Indexed: 10/20/2022]
Affiliation(s)
- Marie N Kolopp-Sarda
- Immunogenomics and Inflammation Research Unit, University of Lyon, Lyon, France; Immunology Laboratory, Hospices Civils de Lyon, Lyon, France
| | - Pierre Miossec
- Immunogenomics and Inflammation Research Unit, University of Lyon, Lyon, France; Department of Immunology and Rheumatology, Clinical Immunology Unit, Hospices Civils de Lyon, Lyon, France.
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20
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Napodano C, Gulli F, Rapaccini GL, Marino M, Basile U. Cryoglobulins: Identification, classification, and novel biomarkers of mysterious proteins. Adv Clin Chem 2021; 104:299-340. [PMID: 34462057 PMCID: PMC7604189 DOI: 10.1016/bs.acc.2020.09.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Cryoglobulins consist of serum immunoglobulins that precipitate below 37°C and resolubilize upon warming. The clinical triad of cryoglobulinemia usually includes purpura, weakness, and arthralgia. Cryoglobulinemic syndrome, clinically defined as a systemic vasculitis, is associated with chronic infection with hepatitis C virus (HCV) and autoimmune disorders and can evolve into B-cell malignancies. While the current literature about HCV-associated cryoglobulinemia is not very limited, little is known about the immunologic and serologic profiles of affected patients. Therefore, comprehension of the pathogenetic mechanisms underlying cryoprecipitation could be very helpful. Due to the persistence of viral antigenic stimulation, biomarkers to use after the worsening progression of HCV infection to lymphoproliferative and/or autoimmune diseases are widely needed. Laboratory methods used to detect and characterize low concentrations of cryoprecipitates and immunotyping patterns could improve patient management. The most critical factor affecting cryoglobulin testing is that the pre-analytical phase is not fully completed at 37°C.
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Affiliation(s)
- Cecilia Napodano
- Dipartimento di Scienze Mediche e Chirurgiche, UOC Gastroenterologia Fondazione Policlinico Universitario "A. Gemelli" I.R.C.C.S., Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Gulli
- Laboratorio di Patologia Clinica, Ospedale Madre Giuseppina Vannini, Rome, Italy
| | - Gian Ludovico Rapaccini
- Dipartimento di Scienze Mediche e Chirurgiche, UOC Gastroenterologia Fondazione Policlinico Universitario "A. Gemelli" I.R.C.C.S., Università Cattolica del Sacro Cuore, Rome, Italy
| | - Mariapaola Marino
- Dipartimento Di Medicina E Chirurgia Traslazionale, Istituto di Patologia Generale, Fondazione Policlinico Universitario "A. Gemelli" I.R.C.C.S., Università Cattolica del Sacro Cuore, Rome, Italy
| | - Umberto Basile
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario "A. Gemelli" I.R.C.C.S., Università Cattolica del Sacro Cuore, Rome, Italy.
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21
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Nusbaum KB, Korman AM, Tyler KH, Kaffenberger JA, Trinidad JC, Dean S, Cataland S, Kaffenberger BH. In vitro diagnostics for the medical dermatologist. Part II: Hypercoagulability tests. J Am Acad Dermatol 2021; 85:301-310. [PMID: 33852929 DOI: 10.1016/j.jaad.2021.03.108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 10/21/2022]
Abstract
The skin often provides initial clues of hypercoagulability with features such as livedo reticularis, livedo racemosa, retiform purpura, necrosis, and ulcerations. Because these cutaneous manifestations are nonspecific, laboratory testing is often needed to evaluate for underlying causes of hypercoagulability. Importantly, these disorders are reported to be the most common mimicker, resulting in an erroneous diagnosis of pyoderma gangrenosum. Understanding inherent properties of, and indications for, available tests is necessary for appropriate ordering and interpretation of results. Additionally, ordering of these tests in an indiscriminate manner may lead to inaccurate results, complicating the interpretation and approach to management. This second article in this continuing medical education series summarizes information on methodology, test characteristics, and limitations of several in vitro laboratory tests used for the work up of hypercoagulability and vasculopathic disease as it pertains to dermatologic disease.
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Affiliation(s)
| | - Abraham M Korman
- Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Kelly H Tyler
- Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Jessica A Kaffenberger
- Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - John C Trinidad
- Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Steven Dean
- Division of Cardiovascular Medicine, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Spero Cataland
- Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Benjamin H Kaffenberger
- Division of Dermatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
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22
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Kolopp-Sarda MN, Miossec P. Cryoglobulinemic vasculitis: pathophysiological mechanisms and diagnosis. Curr Opin Rheumatol 2021; 33:1-7. [PMID: 33186245 DOI: 10.1097/bor.0000000000000757] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
PURPOSE OF REVIEW Cryoglobulins (CG) are immunoglobulins that precipitate in the cold, and dissolve at 37°C. In vivo, in cold exposed tissues and organs, they can induce vasculitis and occlusive vasculopathy after deposition on vascular endothelium under low temperature and high concentration conditions. Clinical manifestations are cutaneous (purpura, ulcers, vasomotor symptoms, and livedo reticularis), rheumatological (arthralgia and arthritis), and peripheral neuropathy (paresthesia and pain in the lower limbs). In profound organs such as the kidneys, CG deposition is less temperature-dependent, favored by local protein and anion concentrations, and can lead to glomerulonephritis. This review will focus on cryoglobulinemic vasculitis and vascular lesion, and their diagnosis. RECENT FINDINGS The mechanisms of vascular lesions of pathogenic CG in function of CG type and their characteristics are better defined. Optimal conditions for CG detection are critical. The importance of looking for underlying diseases, especially hepatitis C virus status in mixed CG, is reminded. SUMMARY A decision diagram for CG vasculitis diagnosis based on clinical and biological parameters is proposed.
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Affiliation(s)
- Marie N Kolopp-Sarda
- Immunogenomics and inflammation research Unit EA 4130, University of Lyon
- Immunology Laboratory
| | - Pierre Miossec
- Immunogenomics and inflammation research Unit EA 4130, University of Lyon
- Department of Immunology and Rheumatology, Clinical Immunology Unit, Hospices Civils de Lyon, Lyon, France
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Cryoglobulinemic vasculitis in primary Sjögren's Syndrome: Clinical presentation, association with lymphoma and comparison with Hepatitis C-related disease. Semin Arthritis Rheum 2020; 50:846-853. [PMID: 32896698 DOI: 10.1016/j.semarthrit.2020.07.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/17/2020] [Accepted: 07/23/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To describe the clinical spectrum of cryoglobulinemic vasculitis (CV) in primary Sjögren's syndrome (pSS), investigate its relation to lymphoma and identify the differences with hepatitis C virus (HCV) related CV. METHODS From a multicentre study population of consecutive pSS patients, those who had been evaluated for cryoglobulins and fulfilled the 2011 classification criteria for CV were identified retrospectively. pSS-CV patients were matched with pSS patients without cryoglobulins (1:2) and HCV-CV patients (1:1). Clinical, laboratory and outcome features were analyzed. A data driven logistic regression model was applied for pSS-CV patients and their pSS cryoglobulin negative controls to identify independent features associated with lymphoma. RESULTS 1083 pSS patients were tested for cryoglobulins. 115 (10.6%) had cryoglobulinemia and 71 (6.5%) fulfilled the classification criteria for CV. pSS-CV patients had higher frequency of extraglandular manifestations and lymphoma (OR=9.87, 95% CI: 4.7-20.9) compared to pSS patients without cryoglobulins. Purpura was the commonest vasculitic manifestation (90%), presenting at disease onset in 39% of patients. One third of pSS-CV patients developed B-cell lymphoma within the first 5 years of CV course, with cryoglobulinemia being the strongest independent lymphoma associated feature. Compared to HCV-CV patients, pSS-CV individuals displayed more frequently lymphadenopathy, type II IgMk cryoglobulins and lymphoma (OR = 6.12, 95% CI: 2.7-14.4) and less frequently C4 hypocomplementemia and peripheral neuropathy. CONCLUSION pSS-CV has a severe clinical course, overshadowing the typical clinical manifestations of pSS and higher risk for early lymphoma development compared to HCV related CV. Though infrequent, pSS-CV constitutes a distinct severe clinical phenotype of pSS.
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24
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Flavell AL, Fullinfaw RO, Smith ER, Holt SG, Finlay MJ, Barbour TD. Noninfectious mixed cryoglobulinaemic glomerulonephritis and monoclonal gammopathy of undetermined significance: a coincidental association? BMC Nephrol 2020; 21:293. [PMID: 32703171 PMCID: PMC7376917 DOI: 10.1186/s12882-020-01941-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Accepted: 07/09/2020] [Indexed: 12/18/2022] Open
Abstract
Background Cryoglobulins are cold-precipitable immunoglobulins that may cause systemic vasculitis including cryoglobulinaemic glomerulonephritis (CGN). Type 1 cryoglobulins consist of isolated monoclonal immunoglobulin (mIg), whereas mixed cryoglobulins are typically immune complexes comprising either monoclonal (type 2) or polyclonal (type 3) Ig with rheumatoid activity against polyclonal IgG. Only CGN related to type 1 cryoglobulins has been clearly associated with monoclonal gammopathy of undetermined significance (MGUS) using the conventional serum-, urine- or tissue-based methods of paraprotein detection. Case presentation We present four patients with noninfectious mixed (type 2 or 3) CGN and MGUS. Two patients had type 2 cryoglobulinaemia, one had type 3 cryoglobulinaemia, and one lacked definitive typing of the serum cryoprecipitate. The serum monoclonal band was IgM-κ in all four cases. Treatments included corticosteroids, cyclophosphamide, plasma exchange, and rituximab. At median 3.5 years’ follow-up, no patient had developed a haematological malignancy or advanced chronic kidney disease. Other potential causes of mixed cryoglobulinaemia were also present in our cohort, notably primary Sjögren’s syndrome in three cases. Conclusion Our study raises questions regarding the current designation of type 2 CGN as a monoclonal gammopathy of renal significance, and the role of clonally directed therapies for noninfectious mixed CGN outside the setting of haematological malignancy.
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Affiliation(s)
- Adam L Flavell
- Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia.
| | - Robert O Fullinfaw
- Department of Chemical Pathology, The Royal Melbourne Hospital, Parkville, Australia
| | - Edward R Smith
- Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia.,Department of Medicine, The University of Melbourne, Melbourne, Australia
| | - Stephen G Holt
- Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia.,Department of Medicine, The University of Melbourne, Melbourne, Australia
| | - Moira J Finlay
- Department of Medicine, The University of Melbourne, Melbourne, Australia.,Department of Anatomical Pathology, The Royal Melbourne Hospital, Parkville, Australia
| | - Thomas D Barbour
- Department of Nephrology, The Royal Melbourne Hospital, Parkville, Australia.,Department of Medicine, The University of Melbourne, Melbourne, Australia
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Natali P, Debbia D, Trenti T, Galassi G, Chester J, Sandri G, Mascia MT. Frequency and Results of Cryoglobulin Retesting in 4,963 Patients: Comment on the Article by Kolopp-Sarda et al. Arthritis Rheumatol 2020; 72:1955-1956. [PMID: 32648698 DOI: 10.1002/art.41434] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/07/2020] [Indexed: 01/14/2023]
Affiliation(s)
- Patrizia Natali
- University Hospital of Modena, Italy and Local Health Unit of Modena, Italy
| | - Daria Debbia
- University Hospital of Modena, Italy and Local Health Unit of Modena, Italy
| | - Tommaso Trenti
- University Hospital of Modena, Italy and Local Health Unit of Modena, Italy
| | - Giuliana Galassi
- University of Modena and Reggio Emilia Modena, Italy, on behalf of the Italian Group for the Study of Cryoglobulinemia (GISC) of Modena, Italy
| | - Johanna Chester
- University of Modena and Reggio Emilia Modena, Italy, on behalf of the Italian Group for the Study of Cryoglobulinemia (GISC) of Modena, Italy
| | - Gilda Sandri
- University of Modena and Reggio Emilia Modena, Italy, on behalf of the Italian Group for the Study of Cryoglobulinemia (GISC) of Modena, Italy
| | - Maria T Mascia
- University of Modena and Reggio Emilia Modena, Italy, on behalf of the Italian Group for the Study of Cryoglobulinemia (GISC) of Modena, Italy
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Ralli M, Campo F, Angeletti D, Minni A, Artico M, Greco A, Polimeni A, de Vincentiis M. Pathophysiology and therapy of systemic vasculitides. EXCLI JOURNAL 2020; 19:817-854. [PMID: 32665772 PMCID: PMC7355154 DOI: 10.17179/excli2020-1512] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 06/15/2020] [Indexed: 12/14/2022]
Abstract
Systemic vasculitides represent uncommon conditions characterized by the inflammation of blood vessels that can lead to different complex disorders limited to one organ or potentially involving multiple organs and systems. Systemic vasculitides are classified according to the diameter of the vessel that they mainly affect (small, medium, large, or variable). The pathogenetic mechanisms of systemic vasculitides are still partly unknown, as well as their genetic basis. For most of the primary systemic vasculitides, a single gold standard test is not available, and diagnosis is often made after having ruled out other mimicking conditions. Current research has focused on new management protocol and therapeutic strategies aimed at improving long-term patient outcomes and avoiding progression to multiorgan failure with irreversible damage. In this narrative review, authors describe different forms of systemic vasculitides through a review of the literature, with the aim of highlighting the current knowledge and recent findings on etiopathogenesis, diagnosis and therapy.
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Affiliation(s)
- Massimo Ralli
- Department of Sense Organs, Sapienza University of Rome, Italy
| | - Flaminia Campo
- Department of Sense Organs, Sapienza University of Rome, Italy
| | | | - Antonio Minni
- Department of Sense Organs, Sapienza University of Rome, Italy
| | - Marco Artico
- Department of Sense Organs, Sapienza University of Rome, Italy
| | - Antonio Greco
- Department of Sense Organs, Sapienza University of Rome, Italy
| | - Antonella Polimeni
- Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Italy
| | - Marco de Vincentiis
- Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Italy
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Wheeler RD, Escaron CJ, Sheldon J. A simple method for maintaining sample temperature during collection of samples for cryoprotein studies. Ann Clin Biochem 2020; 57:397-398. [PMID: 32475126 DOI: 10.1177/0004563220928099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Rachel D Wheeler
- Protein Reference Unit, South West London Pathology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Claire J Escaron
- Protein Reference Unit, South West London Pathology, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Joanna Sheldon
- Protein Reference Unit, South West London Pathology, St George's University Hospitals NHS Foundation Trust, London, UK
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28
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Taher J, Chen C, Kulasingam V. A Puzzling Case of Hyperviscosity Syndrome. J Appl Lab Med 2020; 5:209-213. [PMID: 31662415 DOI: 10.1373/jalm.2019.029157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 04/23/2019] [Indexed: 11/06/2022]
Affiliation(s)
- Jennifer Taher
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Christine Chen
- Ontario Cancer Institute, University Health Network, Toronto, Canada
| | - Vathany Kulasingam
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.,Department of Clinical Biochemistry, University Health Network, Toronto, Canada
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Mariscal-Rodríguez A, Villar Guimerans L, López-Trascasa M, Hernández González M, Moga Naranjo E. Guía de laboratorio para el diagnóstico de pacientes con síndrome crioglobulinémico. Rev Clin Esp 2019; 219:505-513. [DOI: 10.1016/j.rce.2018.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 10/25/2018] [Indexed: 11/29/2022]
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30
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Laboratory guidelines for the diagnosis of patients with cryoglobulinemic syndrome. Rev Clin Esp 2019. [DOI: 10.1016/j.rceng.2019.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Abstract
PURPOSE OF THE REVIEW Cryoglobulins are immunoglobulins with the ability to precipitate at temperatures <37 °C. They are related to hematological disorders, infections [especially hepatitis C virus (HCV)], and autoimmune diseases. In this article, the state of the art on Cryoglobulinemic Vasculitis (CV), in a helpful and schematic way, with a special focus on HCV related Mixed Cryoglobulinemia treatment are reviewed. RECENT FINDINGS Direct - acting antivirals (DAA) against HCV have emerged as an important key in HCV treatment to related Cryoglobulinemic Vasculitis, and should be kept in mind as the initial treatment in non-severe manifestations. On the other hand, a recent consensus panel has published their recommendations for treatment in severe and life threatening manifestations of Mixed Cryoglobulinemias. HCV-Cryoglobulinemic vasculitis is the most frequent form of CV. There are new treatment options in HCV-CV with DAA, with an important number of patients achieving complete response and sustained virologic response (SVR). In cases of severe forms of CV, treatment with Rituximab and PLEX are options. The lack of data on maintenance therapy could impulse future studies in this setting.
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Affiliation(s)
- Alejandro Fuentes
- Departamento de Inmunología clínica y Reumatología, Pontificia Universidad Católica de Chile, Diagonal Paraguay, #362, Santiago, Chile
| | - Claudia Mardones
- Departamento de Inmunología clínica y Reumatología, Pontificia Universidad Católica de Chile, Diagonal Paraguay, #362, Santiago, Chile
| | - Paula I Burgos
- Departamento de Inmunología clínica y Reumatología, Pontificia Universidad Católica de Chile, Diagonal Paraguay, #362, Santiago, Chile.
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Kolopp-Sarda MN, Nombel A, Miossec P. Cryoglobulins Today: Detection and Immunologic Characteristics of 1,675 Positive Samples From 13,439 Patients Obtained Over Six Years. Arthritis Rheumatol 2019; 71:1904-1912. [PMID: 31136095 DOI: 10.1002/art.41003] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 05/23/2019] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Cryoglobulins are cold-precipitating immunoglobulins. Through progress in techniques, we undertook this study to update information on the biologic characteristics of cryoglobulins in a very large population. METHODS A cohort of 13,439 patients was tested for cryoglobulins from January 2010 to December 2016. The analysis included cryoglobulin isotype, clonality, concentration, and IgM rheumatoid factor (IgM-RF) in cryoprecipitate, as well as serum complement and RF. Markers of gammopathy, viral infection, and autoimmunity were also investigated. RESULTS Of the 13,439 patients, 1,675 (12.5%) tested positive for cryoglobulins: 155 patients (9.3%) with type I, 788 (47%) with type II, and 732 (43.7%) with type III cryoglobulins. Nine percent of patients who were retested after initially testing negative for cryoglobulins showed a positive result on a follow-up test (196 of the 2,213 retested patients). In type I cryoglobulins, IgM was more frequent but occurred at lower concentrations than IgG. Mixed cryoglobulins were found in 34.8% of the tested patients who were positive for hepatitis C virus and <5% of those who were positive for hepatitis B virus or HIV. Of the patients with anti-double-stranded DNA, anti-SSA, or anti-cyclic citrullinated peptide autoantibodies, 25.4% tested positive for mixed cryoglobulins, with type III occurring more frequently than type II. Both cryoprecipitate and serum were RF-positive in 21.6% of type II and 10.1% of type III cryoglobulins. A decrease of C4, with or without accompanying decreases of C3 and CH50, was found in 23.6% of cryoglobulin samples. CONCLUSION Obtained with the use of modern assays, our findings from this very large collection of cryoglobulins provide an update on cryoglobulin distribution and characteristics, with minimal selection bias. Despite strict preanalytical conditions, a negative finding for the presence of cryoglobulin must be confirmed in a second sample. RF activity and complement decreases were rarely detected.
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Affiliation(s)
- Marie N Kolopp-Sarda
- Immunogenomics and Inflammation Research Unit EA 4130, University of Lyon and Hospices Civils de Lyon, Lyon, France
| | | | - Pierre Miossec
- Immunogenomics and Inflammation Research Unit EA 4130, University of Lyon and Hospices Civils de Lyon, Lyon, France
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Silva F, Pinto C, Barbosa A, Borges T, Dias C, Almeida J. New insights in cryoglobulinemic vasculitis. J Autoimmun 2019; 105:102313. [PMID: 31383568 DOI: 10.1016/j.jaut.2019.102313] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Revised: 06/24/2019] [Accepted: 07/28/2019] [Indexed: 01/08/2023]
Abstract
Cryoglobulins are antibodies that precipitate at low temperatures and dissolve after rewarming. Cryoglobulinemia refers to the presence of circulating cryoglobulins and generally leads to a systemic inflammatory syndrome characterized by fatigue, arthralgia, purpura, ulcers, neuropathy and/or glomerulonephritis. The disease mainly involves small to medium-sized blood vessels and causes vasculitis due to cryoglobulin-containing immune complexes. Cryoglobulinemia is classified into three types (I, II and III) on the basis of immunoglobulin composition. Predisposing conditions include lymphoproliferative, autoimmune diseases and hepatitis C virus infection. The diagnosis of cryoglobulinemic syndrome is predominantly based on the presence of clinical features and laboratorial demonstration of serum cryoglobulins. The treatment strategy depends on the cause of cryoglobulinemia. For patients with chronic HCV infection, antiviral therapy is indicated. Immunosuppressive or immunomodulatory therapy, including steroids, plasmapheresis and cytotoxic agents, is reserved for organ-threatening manifestations. In this review, we discuss the main clinical presentations, diagnostic approach and treatment options.
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Affiliation(s)
- Filipa Silva
- Internal Medicine Department, Centro Hospitalar Universitário de São João, Porto, Portugal.
| | - Claudemira Pinto
- Internal Medicine Department, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Arsénio Barbosa
- Internal Medicine Department, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Tiago Borges
- Internal Medicine Department, Hospital Privado de Gaia, Gaia, Portugal
| | - Carlos Dias
- Internal Medicine Department, Centro Hospitalar Universitário de São João, Porto, Portugal; Coordinator of Autoimmune Diseases Unit, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Jorge Almeida
- Internal Medicine Department, Centro Hospitalar Universitário de São João, Porto, Portugal
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Chen YP, Cheng H, Rui HL, Dong HR. Cryoglobulinemic vasculitis and glomerulonephritis: concerns in clinical practice. Chin Med J (Engl) 2019; 132:1723-1732. [PMID: 31283654 PMCID: PMC6759094 DOI: 10.1097/cm9.0000000000000325] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE Cryoglobulinemia often causes systemic vasculitis, thereby damaging to skin and internal organs including kidneys, even life-threatening. This review aimed to introduce the advances in understanding, detection, and treatment of this disease in recent years, with a particular concern to clinical practice. DATA SOURCES All the data in this review were from the English or Chinese literature in the PubMed and China National Knowledge Infrastructure databases as of March 2019. STUDY SELECTION This review selected important original articles, meaningful reviews, and some reports on cryoglobulinemia published in recent years and in history, as well as the guidelines for treatment of underlying diseases which lead to cryoglobulinemia. RESULTS Diagnosis of cryoglobulinemia relies on serum cryoglobulin test, in which to ensure that the blood sample temperature is not less than 37°C in the entire pre-analysis phase is the key to avoid false negative results. Cryoglobulinemic vasculitis (Cryo Vas), including cryoglobulinemic glomerulonephritis (Cryo GN), usually occurs in types II and III mixed cryoglobulinemia, and can also be seen in type I cryoglobulinemia caused by monoclonal IgG3 or IgG1. Skin purpura, positive serum rheumatoid factor, and decreased serum levels of C4 and C3 are important clues for prompting types II and III Cryo Vas. Renal biopsy is an important means for diagnosis of Cryo GN, while membranous proliferative GN is the most common pathological type of Cryo GN. In recent years, great advances have been made in the treatment of Cryo Vas and its underlying diseases, and this review has briefly introduced these advances. CONCLUSIONS Laboratory examinations of serum cryoglobulins urgently need standardization. The recent advances in the diagnosis and treatment of Cryo Vas and GN need to be popularized among the clinicians in related disciplines.
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Affiliation(s)
- Yi-Pu Chen
- Division of Nephrology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
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35
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Eloumou SAFB, Mefo'o JPN, Nga WTB, Kenfack GU, Yakana L, Malongue A, Okalla C, Kowo M, Andoulo FA, Tzeuton C, Bidja MSD, Namme HL, Adiogo D, Noah DN. [Cryoglobulin and factors associated with it in patient with anti-hepatitis-C antibodies living in resource-limited countries]. Pan Afr Med J 2019; 33:169. [PMID: 31565130 PMCID: PMC6756798 DOI: 10.11604/pamj.2019.33.169.19162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 06/18/2019] [Indexed: 11/11/2022] Open
Abstract
INTRODUCTION hepatitis C virus (HCV) has several extra-hepatic manifestations including cryoglubulinemia. Cryoglobulinemia is defined as the abnormal presence in the blood of one or several proteins (cryoglobulins) that can precipitate at low temperatures. METHOD We conducted a cross-sectional analytical study in the Laboratory of Biology and in the Unit of Hepatology of the General Hospital in Douala (HGD) over a period of 6 months. All patients agreeing to participate to the study and with anti-hepatitis-C antibodies under treatment or not were enrolled. Cryoglobulins were detected using biuret method and the classification was performed using Brouet immunoelectrophoresis. A multivariate analysis was conducted, confounding factors such as age, sex and the length of time after Hepatitis C Virus screening were adjusted. RESULTS The study enrolled 116 patients. The average age of patients was 58.47±9.95 years. Male sex accounted for 50.86% of cases. Arthralgia was found in 69.80% of cases. Cryoglobulin was found in 63.80% of patients. After adjustment, female sex (OR =2.18; CI 95% [0,97-4,90]; p= 0.059), asthenia alone (OR =2.45;CI 95% [1,04-5,80]; p= 0.041), asthenia combined with arthralgia (OR =2.84;CI 95% [1,13-7, 10]; p= 0.026) and the presence of HCV RNA (OR =2.84;CI 95% [1,13-7,10]; p= 0.028) were factors independently associated with the presence of cryoglobulin. CONCLUSION The prevalence of cryoglobubin is high in patients with anti-hepatitis-C antibodies at the HGD. Simple biological methods are used to detect it. Cryoglobulin test in patients with HCV is essential in resource-limited countries.
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Affiliation(s)
- Servais Albert Fiacre Bagnaka Eloumou
- Service de Médecine Interne, Hôpital Général de Douala, Douala, Cameroun
- Faculté de Médecine et des Sciences Pharmaceutiques, Université de Douala, Douala, Cameroun
| | - Jean Pierre Nda Mefo'o
- Faculté de Médecine et des Sciences Pharmaceutiques, Université de Douala, Douala, Cameroun
- Service de Biologie, Hôpital Général de Douala, Douala, Cameroun
| | - Winnie Tatiana Bekolo Nga
- Service de Médecine Interne, Hôpital Général de Douala, Douala, Cameroun
- Faculté de Médecine et des Sciences Pharmaceutiques, Université de Douala, Douala, Cameroun
| | - Gabin Ulrich Kenfack
- Faculté de Médecine et des Sciences Biomédicales, Université de Yaoundé I, Cameroun
| | - Linus Yakana
- Faculté de Médecine et des Sciences Pharmaceutiques, Université de Douala, Douala, Cameroun
| | - Agnès Malongue
- Service de Médecine Interne, Hôpital Général de Douala, Douala, Cameroun
| | - Cecile Okalla
- Faculté de Médecine et des Sciences Pharmaceutiques, Université de Douala, Douala, Cameroun
- Service de Biologie, Hôpital Général de Douala, Douala, Cameroun
| | - Mathurin Kowo
- Faculté de Médecine et des Sciences Biomédicales, Université de Yaoundé I, Cameroun
| | | | - Christian Tzeuton
- Faculté de Médecine et des Sciences Pharmaceutiques, Université de Douala, Douala, Cameroun
- Centre Médical des Capucines, Douala, Cameroun
| | - Marie Solange Doualla Bidja
- Service de Médecine Interne, Hôpital Général de Douala, Douala, Cameroun
- Faculté de Médecine et des Sciences Pharmaceutiques, Université de Douala, Douala, Cameroun
| | - Henry Luma Namme
- Service de Médecine Interne, Hôpital Général de Douala, Douala, Cameroun
- Faculté de Médecine et des Sciences Biomédicales, Université de Yaoundé I, Cameroun
| | - Dieudonne Adiogo
- Faculté de Médecine et des Sciences Pharmaceutiques, Université de Douala, Douala, Cameroun
| | - Dominique Noah Noah
- Faculté de Médecine et des Sciences Pharmaceutiques, Université de Douala, Douala, Cameroun
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Basile U, Napodano C, Pocino K, Gulli F, Santini SA, Todi L, Marino M, Rapaccini GL. Serological profile of asymptomatic HCV positive patients with low level of cryoglobulins. Biofactors 2019; 45:318-325. [PMID: 30561820 DOI: 10.1002/biof.1485] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 11/09/2018] [Accepted: 11/26/2018] [Indexed: 12/22/2022]
Abstract
Clinical spectrum of hepatitis C virus (HCV)-related cryoglobulinemia varies from an asymptomatic presentation to severe vasculitis and lymphoma. A recent study in HCV-negative patients suggests that low cryoglobulins (CGs) levels are responsible for severe renal and neurological complications. The aim of this study was to identify a panel of serological biomarkers associated with low levels of CGs in HCV-positive patients. We studied a population of 79 untreated patients with chronic HCV infection: 13 naïve patients without CGs; 28 patients with asymptomatic mixed cryoglobulinemia (MC) and low levels of CGs (16/28 with polyclonal type III and 12/28 with microheterogeneous type III CGs); 38 patients with symptomatic MC and high levels of type II CGs. Serum samples were collected and examined for rheumatoid factor (RF) IgG and IgM, free light chains (FLCs) and C3 and C4 complement components. We found that RF-IgG and IgM, free k chains and k+λ were increased while C4 component was reduced, both in symptomatic and asymptomatic patients. Our results suggest that, even in absence of MC symptoms, the low levels of CGs may represent a trigger of activation for immune system in course of HCV infection. The identification of a correlated biomarkers panel could improve the clinical management of these patients and pave the way for target treatment strategies. © 2018 BioFactors, 45(3):318-325, 2019.
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Affiliation(s)
- Umberto Basile
- Dipartimento di Diagnostica per Immagini e Medicina di laboratorio, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Cecilia Napodano
- Dipartimento di Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Krizia Pocino
- Dipartimento di Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Gulli
- Dipartimento di Medicina di Laboratorio, Ospedale generale di zona Madre Giuseppina Vannini, Rome, Italy
| | - Stefano Angelo Santini
- Dipartimento di Diagnostica per Immagini e Medicina di laboratorio, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Laura Todi
- Istituto di Patologia generale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
| | - Mariapaola Marino
- Istituto di Patologia generale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Rome, Italy
| | - Gian Ludovico Rapaccini
- Dipartimento di Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy
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Carubbi F, Alunno A, Cipriani P, Bistoni O, Scipioni R, Liakouli V, Ruscitti P, Berardicurti O, Di Bartolomeo S, Gerli R, Giacomelli R. Laboratory Assessment of Patients with Suspected Rheumatic Musculoskeletal Diseases: Challenges and Pitfalls. Curr Rheumatol Rev 2019; 15:27-43. [PMID: 29557752 DOI: 10.2174/1573397114666180320113603] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 03/14/2018] [Accepted: 03/15/2018] [Indexed: 11/22/2022]
Abstract
Current patient care in rheumatology relies primarily on a combination of traditional clinical assessment and standard laboratory tests. Investigators seek to discover new biomarkers and novel technologies to boost the research in this field. Mechanistic biomarkers such as cytokines, cell types, antibodies, signaling molecules, are rooted in the mechanism underlying the disease and can guide the clinical management of the disease. Conversely, descriptive biomarkers are byproducts of the disease process, depict the state of a disease but are not involved in its pathogenesis. In this article, we reviewed the field of common laboratory biomarkers in rheumatology, highlighting both their descriptive or mechanistic value as well as their role in clinical practice.
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Affiliation(s)
- Francesco Carubbi
- Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila, AQ, Italy.,Department of Medicine, ASL1 Avezzano-Sulmona-L'Aquila, L'Aquila, AQ, Italy
| | - Alessia Alunno
- Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, PG, Italy
| | - Paola Cipriani
- Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila, AQ, Italy
| | - Onelia Bistoni
- Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, PG, Italy
| | - Rosa Scipioni
- Department of Medicine, ASL1 Avezzano-Sulmona-L'Aquila, L'Aquila, AQ, Italy
| | - Valiki Liakouli
- Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila, AQ, Italy
| | - Piero Ruscitti
- Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila, AQ, Italy
| | - Onorina Berardicurti
- Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila, AQ, Italy
| | - Salvatore Di Bartolomeo
- Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila, AQ, Italy
| | - Roberto Gerli
- Rheumatology Unit, Department of Medicine, University of Perugia, Perugia, PG, Italy
| | - Roberto Giacomelli
- Rheumatology Unit, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila, AQ, Italy
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Hegazy MT, Allam WR, Hussein MA, Zoheir N, Quartuccio L, El-Khamisy SF, Ragab G. Increased genomic instability following treatment with direct acting anti-hepatitis C virus drugs. EBioMedicine 2018; 35:106-113. [PMID: 30139628 PMCID: PMC6156732 DOI: 10.1016/j.ebiom.2018.08.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 08/04/2018] [Accepted: 08/05/2018] [Indexed: 12/04/2022] Open
Abstract
Mixed Cryoglobulinemic Vasculitis (MCV) is a prominent extra-hepatic manifestation of Hepatitis C virus (HCV) infection. HCV has been reported to cause B-cell disorders and genomic instability. Here, we investigated B-cell activation and genome stability in HCV-MCV patients receiving the direct antiviral agent, Sofosbuvir, at multiple centers in Egypt. Clinical manifestations in HCV-MCV patients were improved at the end of treatment (EOT), such as purpura (100%), articular manifestations (75%) and neuropathy (68%). Eighteen patients (56%) showed vasculitis relapse after EOT. BAFF and APRIL were higher at EOT and continued to increase one year following treatment onset. Chromosomal breaks were elevated at EOT compared to baseline levels and were sustained at 3 and 6 months post treatment. We report increased expression of DNA genome stability transcripts such as topoisomerase 1 and TDP1 in HCV-MCV patients after treatment, which continued to increase at 12 months from treatment onset. This data suggest that B-cell activation and DNA damage are important determinants of HCV-MCV treatment outcomes.
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Affiliation(s)
- Mohamed Tharwat Hegazy
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt
| | | | - Mohamed A Hussein
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt
| | - Naguib Zoheir
- Clinical and Chemical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Luca Quartuccio
- Clinic of Rheumatology, Department of Medical Area (DAME), University Hospital "Santa Maria della Misericordia", University of Udine, Udine, Italy
| | - Sherif F El-Khamisy
- Center for Genomics, Zewail City of Science and Technology, Giza, Egypt; Krebs Institute, Department of Molecular Biology and Biotechnology, University of Sheffield, Sheffield, S10 2TN, UK.
| | - Gaafar Ragab
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Giza, Egypt.
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Spatola L, Generali E, Angelini C, Badalamenti S, Selmi C. HCV-negative mixed cryoglobulinemia and kidney involvement: in-depth review on physiopathological and histological bases. Clin Exp Med 2018; 18:465-471. [PMID: 29956004 DOI: 10.1007/s10238-018-0514-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Accepted: 06/21/2018] [Indexed: 11/28/2022]
Abstract
Type II mixed cryoglobulinemia without evidence of HCV infection but rather with renal involvement has been occasionally described. The pathogenesis of cryoglobulinemic kidney disease is most likely related to immune complex deposition including cryoglobulins, and cryoaggregation after cold exposure could play a pivotal role in clinical expression of cryoglobulinemia. In these cases, acute kidney injury and proteinuria remain the most frequent clinical expression of a cryoglobulinemic glomerulonephritis. Type II cryoglobulinemia with the laboratory finding of both monoclonal and polyclonal cryoglobulins is the most prevalent bio-humoral pattern among HCV-negative phenotypes with renal involvement, while type III cryoglobulinemia with polyclonal Ig is rare. Histological data in renal biopsies support the hypothesis that regardless of the HCV status cryoglobulinemia vasculitis share the same frequent pathological finding of membranoproliferative glomerulonephritides, but other histological patterns have also been observed in a minority of cases. In HCV-negative mixed cryoglobulinaemia, the paraneoplastic origin of the immune dysfunction should be ruled out and sporadic cases have been reported, while there is no cumulative evidence on the prevalence of these tumour-associated manifestations. Moving from the classification criteria and the etiopathogenesis of mixed cryoglobulinaemia, we provide a comprehensive review of the literature on the appearance of the disease with kidney injury in association with malignancies or autoimmune disorders without HCV coexistence.
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Affiliation(s)
- Leonardo Spatola
- Unit of Nephrology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy.
| | - Elena Generali
- Unit of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Claudio Angelini
- Unit of Nephrology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Salvatore Badalamenti
- Unit of Nephrology, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Carlo Selmi
- Unit of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.,BIOMETRA Department, University of Milan, Milan, Italy
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Khalighi MA, Al-Rabadi L, Chalasani M, Smith M, Kakani S, Revelo MP, Meehan SM. Staphylococcal Infection-Related Glomerulonephritis With Cryoglobulinemic Features. Kidney Int Rep 2018; 3:1128-1134. [PMID: 30197979 PMCID: PMC6127436 DOI: 10.1016/j.ekir.2018.05.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 05/07/2018] [Accepted: 05/21/2018] [Indexed: 12/11/2022] Open
Abstract
Introduction Staphylococcal infection–related glomerulonephritis (GN) has been shown to represent a unique form of infection-related GN that contains IgA-dominant deposits and is often seen concurrently with the bacterial infection. Biopsies commonly reveal an endocapillary proliferative and/or exudative or mesangial proliferative GN. Rare cases have been reported to show cryoglobulin-like features, including hyaline pseudothrombi and wireloop deposits; however, detailed characterization of these cases is lacking. Methods The pathology archives from the University of Utah and Sharp Memorial Hospital were reviewed from January 2016 to September 2017 in search of cases with GN containing IgA-dominant deposits and features of cryoglobulinemia. Results Of 1965 native kidney biopsies, 5 showed IgA-dominant GN with cryoglobulinemic features. All patients had active staphylococcal infections at the time of biopsy. All presented with acute kidney injury (serum creatinine range: 1.7−6 mg/dl), and all had proteinuria and hematuria. All biopsies showed exudative GN, and 4 biopsies had focal crescents. All had focally prominent hyaline pseudothrombi with or without wireloop deposits, and all showed co-dominant staining for IgA and C3 on immunofluorescence microscopy. Serologic testing for cryoglobulinemia was performed in 3 patients and was transiently positive in 1 patient. Four patients required hemodialysis at last follow-up, whereas 1 patient returned to baseline kidney function. Conclusion IgA-dominant GN with cryoglobulinemic features is an uncommon but severe form of glomerular injury in patients with staphylococcal infections. Four of 5 patients had crescentic glomerular injuries, all of whom required hemodialysis at last follow-up. Patients with IgA-dominant GN with features of cryoglobulinemia should be evaluated for active staphylococcal infection.
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Affiliation(s)
- Mazdak A Khalighi
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA
| | - Laith Al-Rabadi
- Department of Nephrology, University of Utah, Salt Lake City, Utah, USA
| | - Meghana Chalasani
- Department of Nephrology, University of Utah, Salt Lake City, Utah, USA
| | - Mark Smith
- Nephrology Associates, PC, Augusta, Georgia, USA
| | - Siddhartha Kakani
- Department of Nephrology, University of Utah, Salt Lake City, Utah, USA
| | - Monica P Revelo
- Department of Pathology, University of Utah, Salt Lake City, Utah, USA
| | - Shane M Meehan
- Department of Pathology, Sharp Memorial Hospital, San Diego, California, USA
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Kolopp-Sarda MN, Miossec P. Cryoglobulins: An update on detection, mechanisms and clinical contribution. Autoimmun Rev 2018. [PMID: 29526627 DOI: 10.1016/j.autrev.2017.11.035] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cryoglobulins are immunoglobulins precipitating in cold condition. They are classified in 3 types according to the Brouet classification and may lead to vasculitis of small and medium size vessels. Vasculitis is related to vessel obstruction by monoclonal cryoglobulin aggregates in type I cryoglobulins and immune complex deposition in type II and III mixed cryoglobulins. This phenomenon is favored by low temperature, especially in skin, joints, and peripheral nerves, or increased cryoglobulin concentration in kidneys. For their detection, collection and clotting at 37°C are critical pre-analytical conditions. Cryoglobulin characterization and quantification are important to identify the underlying disease. Since detection and identification of cryoglobulins lack standardization, a protocol for such detection, characterization and quantification is proposed.
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Affiliation(s)
- Marie-Nathalie Kolopp-Sarda
- Department of Immunology and Rheumatology, Immunogenomics and inflammation research Unit EA 4130, University of Lyon, Lyon, France; Immunology Laboratory, University Hospital Lyon, France
| | - Pierre Miossec
- Department of Immunology and Rheumatology, Immunogenomics and inflammation research Unit EA 4130, University of Lyon, Lyon, France.
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Bunchorntavakul C, Mitrani R, Reddy KR. Advances in HCV and Cryoglobulinemic Vasculitis in the Era of DAAs: Are We at the End of the Road? J Clin Exp Hepatol 2018; 8:81-94. [PMID: 29743799 PMCID: PMC5938331 DOI: 10.1016/j.jceh.2017.11.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 11/30/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C Virus (HCV)-related Mixed Cryoglobulinemia (MC) is a unique condition with complex pathogenesis that involves HCV antigen-driven B-lymphocyte clonal proliferation and mutagenesis. Clinical spectrum of MC ranges from asymptomatic state to clinically-apparent vasculitis involving multiple organs. In the era of Direct-Acting Antiviral (DAA) therapy, patients with HCV-related MC achieve high rates of viral clearance that is commonly accompanied by an improvement in clinical symptoms as well as immunological profiles. Rituximab, either alone or in combination with DAA, has also been shown to be effective. Nevertheless, there have been limited and somewhat conflicting data, particularly over the long-term, regarding the rate and degree of clinical response of MC following DAA therapy. It appears that we have come quite a long way in the last decade with this condition. As with non-MC related HCV, undoubtedly long term outcome data will be forthcoming over the next few years. As we move forward successful therapy of HCV is not likely to be a challenge in contrast to access to therapy.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand
| | - Robert Mitrani
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - K. Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
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Basile U, Gulli F, Gragnani L, Fognani E, Napodano C, Pocino K, Zignego AL, Rapaccini GL. IgG3 subclass: A possible trigger of mixed cryoglobulin cascade in hepatitis C virus chronic infection. Dig Liver Dis 2017; 49:1233-1239. [PMID: 28688880 DOI: 10.1016/j.dld.2017.06.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 06/03/2017] [Accepted: 06/06/2017] [Indexed: 12/11/2022]
Abstract
HCV is a hepatotropic and lymphotropic virus and is the most frequent cause of "benign" mono-oligoclonal B-lymphocyte proliferation, observed in mixed cryoglobulinemia (MC). The study aims to investigate the presence, prevalence and characteristics of the subclasses of cryoglobulins in HCV-patients to look for a relationship with MC. Fifty HCV-infected patients with cryoglobulins were enrolled. IgG subclasses were characterized in cryoprecipitate, and serum IgG and IgM Rheumatoid Factor (RF) were determined. Patients were stratified into two subgroups according to the presence of IgG3 subclass. Differences were observed in supernatant IgM, IgG3-positive and IgG3-negative patients with a higher IgM concentration in the IgG3-negative cohort (p=0.03). Higher IgM-RF was detected in the IgG3-negative group (p=0.01). IgG3-positive group showed higher IgG-RF compared to the IgG3-negative group (p<0.0001). IgG3-negative/monoclonal-IgM patients had higher cryocrit compared to IgG3-negative/polyclonal-IgM patients (p<0.01). C4 levels were higher in the polyclonal-IgM group compared to monoclonal-IgM group (p<0.01). We speculate that cryoglobulins are part of a progressive clonal selection process in which, B-cells are stimulated to produce oligoclonal IgG3 with RF activity. The persistence of the antigenic stimulus elicits the production of polyclonal IgM-RF and subsequently the formation of oligoclonal IgG/polyclonal IgM containing cryoglobulins. In the last stage, a monoclonal IgM-RF clone is formed which may coexist with a monoclonal IgG3-RF clone.
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Affiliation(s)
- Umberto Basile
- Department of Laboratory Medicine, Catholic University of the Sacred Heart, Largo A. Gemelli, 8, 00168 Rome, Italy
| | - Francesca Gulli
- Department of Laboratory Medicine, Madre Giuseppina Vannini Hospital, via Acqua Bullicante, 4, 00177 Rome, Italy
| | - Laura Gragnani
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla, 3, 50134 Florence, Italy.
| | - Elisa Fognani
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla, 3, 50134 Florence, Italy
| | - Cecilia Napodano
- Department of Laboratory Medicine, Catholic University of the Sacred Heart, Largo A. Gemelli, 8, 00168 Rome, Italy
| | - Krizia Pocino
- Department of Laboratory Medicine, Catholic University of the Sacred Heart, Largo A. Gemelli, 8, 00168 Rome, Italy
| | - Anna Linda Zignego
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, Department of Experimental and Clinical Medicine, University of Florence, Largo Brambilla, 3, 50134 Florence, Italy
| | - Gian Ludovico Rapaccini
- Institute of Internal Medicine, Catholic University of the Sacred Heart, Largo A. Gemelli, 00168 Rome, Italy
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Hsu JL, Liao MF, Hsu HC, Weng YC, Lo AL, Chang KH, Chang HS, Kuo HC, Huang CC, Ro LS. A prospective, observational study of patients with uncommon distal symmetric painful small-fiber neuropathy. PLoS One 2017; 12:e0183948. [PMID: 28957343 PMCID: PMC5619719 DOI: 10.1371/journal.pone.0183948] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 08/15/2017] [Indexed: 01/11/2023] Open
Abstract
Objective To investigate the clinical characteristics of patients with uncommon distal symmetric painful small-fiber neuropathy (DSPSFN). Methods From September 2012 to September 2014, participants between 18–70 years of age that had DSPSFN defined by clinical signs/symptoms and ID pain > 2 or DN4 > 4 on questionnaires for more than 1 month were included. Participants who had previous historical or laboratory evidence of common etiologies of DSPSFN were excluded. Enzyme activity and genetic studies for Fabry diseaseand familial amyloid polyneuropathy were performed after participants fulfilled the inclusion and exclusion criteria. The cryoglobulin test, autoantibodies studies and electrophysiological studies were performed in these participants. Results In total, 100 cases were enrolled in the current study. Three cases of subclinical diabetes mellitus and two cases of fibromyalgia were found. Fabry disease (1%) and familial amyloid polyneuropathy (3%) with Ala97Ser transthyretin (TTR) mutations were also detected. The cryoglobulin test was positive in 30% of participants, and these participants had higher DN4 scores than the negative group. In the autoantibodies studies, 59% of the participants had abnormal anti-Ro/SSA and/or anti-La/SSB antibodies. Conclusions Cryoglobulinemia is not a rare etiology of uncommon DSPSFN. The long-term prognosis is quite good in these participants. From our structuralized protocol, Fabry disease and familial amyloid polyneuropathy could be easily detected in these cases of uncommon DSPSFN.
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Affiliation(s)
- Jung-Lung Hsu
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, Taipei, Taiwan
- Taipei Medical University, Graduate Institute of Humanities in Medicine, Taipei, Taiwan
- Taipei Medical University Research Center for Brain and Consciousness, Shuang Ho Hospital, New Taipei City, Taiwan
| | - Ming-Feng Liao
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, Taipei, Taiwan
| | - Hui-Ching Hsu
- Department of Traditional Chinese Medicine, Division of Chinese Acupuncture and Traumatology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, Taipei, Taiwan
| | - Yi-Ching Weng
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, Taipei, Taiwan
| | - Ai-Lun Lo
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, Taipei, Taiwan
| | - Kuo-Hsuan Chang
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, Taipei, Taiwan
| | - Hong-Shiu Chang
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, Taipei, Taiwan
| | - Hung-Chou Kuo
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, Taipei, Taiwan
| | - Chin-Chang Huang
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, Taipei, Taiwan
| | - Long-Sun Ro
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and Chang Gung University College of Medicine, Taipei, Taiwan
- * E-mail:
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Abstract
PURPOSE To report a unique case of peripheral ulcerative keratitis secondary to hepatitis B virus (HBV)-associated cryoglobulinemia and vasculitis and its pharmacological and surgical treatment and 2-year follow-up. METHODS A 52-year-old woman presented with unilateral eye pain and photophobia, arthralgia, remnants of a maculopapular rash, and subsequently facial numbness several weeks later. Her best spectacle-corrected visual acuity (BSCVA) in the affected eye was 20/80. Slit-lamp examination revealed severe superior corneal thinning without infiltrate. Corneal ulceration worsened until 10% of the cornea remained. Laboratory workup was positive for rheumatoid factor and revealed significantly decreased C4 complement, and HBV serology was positive. RESULTS Clinical history, examinations, and laboratory results suggest HBV-associated cryoglobulinemia and vasculitis. Management included prednisone, cyclophosphamide, and mycophenolate mofetil for immunosuppression and tenofovir for HBV treatment. Conjunctival resection and a glue patch were used to reduce inflammation and stabilize corneal melt. BSCVA improved after treatment was initiated. Two years after initial presentation, her BSCVA is 20/30, significantly improved from her vision at presentation. CONCLUSIONS Diagnosis of peripheral ulcerative keratitis requires thorough history and physical examinations given the numerous causes. Prompt treatment including immunosuppressive medication and, in this case, antiviral medication is crucial to preventing serious visual consequences including corneal perforation and blindness.
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46
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Tang DH, Ye YS, Wang CY, Zheng H, Li ZL, Ma KL. Mixed cryoglobulinaemia in a rhesus macaque (Macaca mulatta). J Med Primatol 2017; 46:352-355. [PMID: 28744862 DOI: 10.1111/jmp.12292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2017] [Indexed: 10/19/2022]
Abstract
We report cryoglobulinaemia (CG) in a rhesus macaque whose serum sample was gel-like at <37°C and resolubilised upon warming. Mixed CG was diagnosed using serum protein electrophoresis and serum immunofixation electrophoresis. Renal damage and arthrophyma were observed during necropsy. This is the first report of CG in a non-human primate.
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Affiliation(s)
- Dong-Hong Tang
- Medical Primate Research Centre of China, Institute of Medical Biology, Chinese Academy of Medical Sciences/Peking Union Medical College, Kunming, China
| | - You-Song Ye
- Medical Primate Research Centre of China, Institute of Medical Biology, Chinese Academy of Medical Sciences/Peking Union Medical College, Kunming, China
| | - Chen-Yun Wang
- Medical Primate Research Centre of China, Institute of Medical Biology, Chinese Academy of Medical Sciences/Peking Union Medical College, Kunming, China
| | - Hong Zheng
- Kunming Medical University, Kunming, China
| | - Zhe-Li Li
- Medical Primate Research Centre of China, Institute of Medical Biology, Chinese Academy of Medical Sciences/Peking Union Medical College, Kunming, China
| | - Kai-Li Ma
- Medical Primate Research Centre of China, Institute of Medical Biology, Chinese Academy of Medical Sciences/Peking Union Medical College, Kunming, China
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47
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Ali MA, Kayani WZ, Linzie BM, Punjabi GV, Wetmore JB. Myopericarditis in a patient with hepatitis C and cryoglobulinemic renal disease. Clin Case Rep 2017; 5:616-620. [PMID: 28469862 PMCID: PMC5412876 DOI: 10.1002/ccr3.788] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 10/05/2016] [Accepted: 11/22/2016] [Indexed: 12/12/2022] Open
Abstract
Although cryoglobulinemia is a well‐appreciated complication of hepatitis C (HC), myopericarditis with resulting pericardial effusion is extremely rare, especially in the absence of a liver transplant. In patients with HC, pericardial effusion with impending tamponade can be a florid and potentially life‐threatening manifestation of multiorgan cryoglobulinemic disease.
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Affiliation(s)
- Mohamoud A Ali
- Department of Medicine Hennepin County Medical Center Minneapolis Minnesota USA
| | - Waqas Z Kayani
- Department of Family & Community Medicine UND School of Medicine and Health Sciences Minot North Dakota USA
| | - Bradley M Linzie
- Department of Pathology Hennepin County Medical Center Minneapolis Minnesota USA
| | - Gopal V Punjabi
- Department of Radiology Hennepin County Medical Center Minneapolis Minnesota USA
| | - James B Wetmore
- Division of Nephrology Hennepin County Medical Center Minneapolis Minnesota USA.,Chronic Disease Research Group Minneapolis Minnesota USA
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Cryoglobulin Test and Cryoglobulinemia Hepatitis C-Virus Related. Mediterr J Hematol Infect Dis 2017; 9:e2017007. [PMID: 28101312 PMCID: PMC5224812 DOI: 10.4084/mjhid.2017.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Accepted: 12/12/2016] [Indexed: 12/14/2022] Open
Abstract
Cryoglobulins are immunoglobulins that precipitate in serum at temperatures below 37°C and resolubilize upon warming. The clinical syndrome of cryoglobulinemia usually includes purpura, weakness, and arthralgia, but the underlying disease may also contribute other symptoms. Blood samples for cryoglobulin are collected, transported, clotted and spun at 37°C, before the precipitate is allowed to form when serum is stored at 4°C in a Wintrobe tube for at least seven days. The most critical and confounding factor affecting the cryoglobulin test is when the preanalytical phase is not fully completed at 37°C. The easiest way to quantify cryoglobulins is the cryocrit estimate. However, this approach has low accuracy and sensitivity. Furthermore, the precipitate should be resolubilized by warming to confirm that it is truly formed of cryoglobulins. The characterization of cryoglobulins requires the precipitate is several times washed, before performing immunofixation, a technique by which cryoglobulins can be classified depending on the characteristics of the detected immunoglobulins. These features imply a pathogenic role of these molecules which are consequently associated with a wide range of symptoms and manifestations. According to the Brouet classification, Cryoglobulins are grouped into three types by the immunochemical properties of immunoglobulins in the cryoprecipitate. The aim of this paper is to review the major aspects of cryoglobulinemia and the laboratory techniques used to detect and characterize cryoglobulins, taking into consideration the presence and consequences of cryoglobulinemia in Hepatitis C Virus (HCV) infection.
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Toyonaga E, Iwata H, Hotta M, Yoshimoto N, Izumi K, Shimizu H. Keep It Cool: Cryoglobulinemic Purpura. Am J Med 2016; 129:1163-1165. [PMID: 27566501 DOI: 10.1016/j.amjmed.2016.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 08/04/2016] [Accepted: 08/04/2016] [Indexed: 11/20/2022]
Affiliation(s)
- Ellen Toyonaga
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hiroaki Iwata
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
| | - Moeko Hotta
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Norihiro Yoshimoto
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Kentaro Izumi
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hiroshi Shimizu
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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50
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Jacobs JF, Wevers RA, Lefeber DJ, van Scherpenzeel M. Fast, robust and high-resolution glycosylation profiling of intact monoclonal IgG antibodies using nanoLC-chip-QTOF. Clin Chim Acta 2016; 461:90-7. [DOI: 10.1016/j.cca.2016.07.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 07/20/2016] [Accepted: 07/21/2016] [Indexed: 12/31/2022]
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