Classification of diseases with increased immunoglobulins

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Chapter 29	SECTION 6 - Appendices
	Classification of diseases with increased immunoglobulins

Contents 1 29.1. Monoclonal gammopathies 2 29.2. Polyclonal gammopathies 3 References

29.1. Monoclonal gammopathies

In May 2003, The International Myeloma Working Group published a review of the criteria for the diagnosis and classification of monoclonal gammopathies, multiple myeloma (MM) and related disorders ^[1]. The aim was to standardise and simplify previous classification systems and provide easy definitions based on routinely available investigations. A uniform approach should facilitate comparisons of therapeutic trial data. The disease groups are as follows and their definitions are found in the respective chapters of this book.

1. Monoclonal gammopathy of undetermined significance (MGUS). (Chapter 19)
2. Smouldering (asymptomatic) multiple myeloma (SMM) or Durie and Salmon Stage I). (Chapter 14)
3. Symptomatic MM. (Chapters 8, 9, 10, 11, 12 and 13)
4. Nonsecretory multiple myeloma (NSMM). (Chapter 9)
5. Solitary plasmacytoma of bone. (Chapter 18.1)
6. Extramedullary plasmacytoma. (Chapter 18.2)
7. Multiple solitary plasmacytoma. (Chapter 18.3)
8. Plasma cell leukaemia. (Chapter 18.4)

This classification includes the diseases indicated above and other types of monoclonal gammopathies. The distribution of clinical diagnoses in patients with monoclonal gammopathies is discussed further in Section 2. The co-occurrence of monoclonal immunoglobulins with non-malignant conditions is uncommon but a proportion of such patients will contain chance associations with MGUS.

1. Benign (IgG, IgA, IgD, IgM and FLCs)

2. Biclonal and triclonal gammopathies

1. MM (IgG, IgA, IgD, IgE and free k or λ light chains)

a. Overt MM

b. SMM

c. Plasma cell leukaemia

d. NSMM

e. POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes; osteosclerotic myeloma)

2. Plasmacytoma

a. Solitary plasmacytoma of bone

b. Extramedullary plasmacytoma

3. Malignant lymphoproliferative disorders

4. Waldenström’s macroglobulinemia (primary macroglobulinemia)

5. Malignant Lymphoma

6. Chronic lymphocytic leukemia or lymphoproliferative disorders

7. Heavy chain diseases

a. γ heavy chain disease

b. α heavy chain disease

c. μ heavy chain disease

8. Amyloidosis

a. Primary amyloidosis

b. With MM (secondary, localised, and familial amyloidosis have no monoclonal protein)

Lichen myxoedematosus (IgG1), scleroderma, pyoderma gangrenosum, necrobiotic xanthogranuloma, discoid lupus erythematosus, psoriasis, cutaneous lymphoma

AIDS and HIV infection, renal transplantation, bone marrow transplantation

Chronic hepatitis, cirrhosis, primary biliary cirrhosis

Rheumatoid arthritis, inflammatory seronegative polyarthritis, polymyositis (IgGκ), polymyalgia rheumatica, myasthenia gravis, angioneurotic oedema (C1 inactivator deficiency)

29.2. Polyclonal gammopathies

Chronic infections, autoimmune diseases and many tumours cause increases in polyclonal immunoglobulins and presumably polyclonal FLC concentrations (Chapter 21). Skin, pulmonary and gut diseases are more likely to cause increases in IgA concentrations while systemic infections will increase all immunoglobulins but particularly IgG. The percentages indicate the frequency of the various disorders from a retrospective cohort study of 148 patients with polyclonal gammopathy at The Mayo Clinic ^[2]. Clearly, results will vary in different parts of the world.

Sjögren's syndrome, rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease, overlap syndrome, juvenile rheumatoid arthritis, progressive systemic sclerosis, ankylosing spondylitis, fibrosing alveolitis, CREST syndrome, temporal arteritis, Raynaud’s phenomenon, cutaneous vasculitis, familial mediterranean fever, eosinophilic fasciitis and inclusion body myositis.

Autoimmune hepatitis, viral hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, cryptogenic cirrhosis, primary hemochromatosis, ethanol-induced liver injury and α1-antitrypsin deficiency.

Subacute bacterial endocarditis, renal abscess, cystic fibrosis, Whipple's disease, brucellosis, Lyme disease, malaria, worm infestations, tropical splenomegaly syndrome, mycobacterium tuberculosis, mycobacterium leprae, Leishmania organisms, Trypanosoma cruzi, Toxocara canis, HIV-1, varicella and vaccinia.

Pseudolymphoma, Kikuchi disease, malignant lymphoma, Castleman disease, angioimmunoblastic lymphadenopathy with dysproteinemia, large granular lymphocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, plasma cell leukaemia, histiocytosis X, sinus histiocytosis with massive lymphadenopathy, cutaneous eruptive histiocytoma, intracranial plasma cell granulomata, systemic cutaneous plasmacytosis, proteinaceous lymphadenopathy with hypergammaglobulinemia, chronic active EBV infection syndrome and severe autoimmune lymphoproliferative syndrome.

Myelodysplastic syndromes, idiopathic neutropenia, idiopathic thrombocytopenic purpura, severe hemophilia A, Thalassemia major, Sickle cell anemia, benign hypergammaglobulinemic purpura of Waldenström, cryoglobulinemia and Fanconi anemia.

Gastric carcinoma, lung cancer, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer and chondrosarcoma.

Acquired chronic dysimmune demyelinating polyneuropathy, HTLV-1-associated myelopathy, chronic progressive sensory ataxic neuropathy, pure motor neuron disease and plasma cell dyscrasia and microangiopathy of vasa nervorum in dysglobulinemic neuropathy.

Graves’ disease, chronic ulcerative colitis, chronic autoimmune pancreatitis, sarcoidosis, syndrome of IgG2 subclass deficiency, hyper IgE syndrome, hyperimmunoglobulinemia D and periodic fever syndrome.

Aminophenazone, asparaginase, ethotoin, hydralazine hydrochloride, mephenytoin, methadone, oral contraceptives, phenylbutazone and phenytoin.

Gaucher’s disease, Meniére’s disease, cardiac myxoma, asbestos exposure, cryptogenic organising pneumonitis, lymphoid interstitial pneumonia, distal renal tubular acidosis and hyperimmunisation.

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Chapter 30

References