Table 2.

Current pathophysiological classification of the main MGCS-related disorders: cytokine mediated or MGCS due to autoantibody activity, CAP activation, cytokine-mediated, or of unknown mechanism

MechanismMain characteristics of monoclonal gammopathyMain organ(s) involvedReference
Autoantibody activity     
 Type II mixed cryoglobulinemia* Rheumatoid IgM Immune complex–mediated vasculitis; skin +++, kidney, peripheral nerve; may be systemic 28,60  
 C1 inhibitor deficiency C1 inhibitor  Angioedema 25  
 Von Willebrand disease vW factor  Bleeding 26  
 Bullous skin diseases Dermoepidermal junction (collagen VII)  Skin 21  
 Xanthomatosis Various lipoproteins Usually IgG Cholesterol accumulation in macrophages; skin and tendons; other localizations (necrobiotic xanthogranumathosis) 29,30  
 Cold agglutinin disease Red blood cell (Ii) IgM Cold-induced skin manifestations + intravascular hemolysis 27  
 IgM-associated peripheral neuropathy MAG +++ IgM Peripheral nerve; ataxic polyneuropathy (anti-MAG) CANOMAD 22,23  
Gangliosides 
CAP*activation     
 C3 glomerulonephritis Atypical hemolytic-uremic syndrome Mechanism to be determined; autoantibody activity against CAP regulator protein (factor H) in some cases IgG Kidney only Systemic 31,,-34  
Cytokine mediated     
 POEMS syndrome VEGF λ LC (∼100%), Peripheral nerve (100%) and various other manifestations 35,36  
IgA 50% 
Vλ1 (#100%) 
Osteosclerotic bone lesions 
Unknown mechanism     
 Systemic capillary leak syndrome  IgG, IgA (rare) Systemic 45  
 TEMPI syndrome  IgG Systemic 46,47  
 Neutrophilic dermatosis  IgA >80% (except Sweet syndrome) Skin +++; different types and different associated manifestations 39  
 Acquired cutis laxa  Usually IgG; association with γ HCDD Skin +++Other manifestations (lung, digestive tract) 43  
 
 Scleromyxedema  IgG with slow electrophoretic mobility Skin +++; other localizations 40,41,52  
 Scleroedema  IgG Skin only 41  
 Schnitzler syndrome Acquired autoinflammatory syndrome by IL-1 deregulation? IgM Skin +++; systemic symptoms; osteosclerotic bone lesions 44  
 Sporadic late-onset nemaline myopathy   Exclusively muscles (skeletal and possibly cardiac) 48  
MechanismMain characteristics of monoclonal gammopathyMain organ(s) involvedReference
Autoantibody activity     
 Type II mixed cryoglobulinemia* Rheumatoid IgM Immune complex–mediated vasculitis; skin +++, kidney, peripheral nerve; may be systemic 28,60  
 C1 inhibitor deficiency C1 inhibitor  Angioedema 25  
 Von Willebrand disease vW factor  Bleeding 26  
 Bullous skin diseases Dermoepidermal junction (collagen VII)  Skin 21  
 Xanthomatosis Various lipoproteins Usually IgG Cholesterol accumulation in macrophages; skin and tendons; other localizations (necrobiotic xanthogranumathosis) 29,30  
 Cold agglutinin disease Red blood cell (Ii) IgM Cold-induced skin manifestations + intravascular hemolysis 27  
 IgM-associated peripheral neuropathy MAG +++ IgM Peripheral nerve; ataxic polyneuropathy (anti-MAG) CANOMAD 22,23  
Gangliosides 
CAP*activation     
 C3 glomerulonephritis Atypical hemolytic-uremic syndrome Mechanism to be determined; autoantibody activity against CAP regulator protein (factor H) in some cases IgG Kidney only Systemic 31,,-34  
Cytokine mediated     
 POEMS syndrome VEGF λ LC (∼100%), Peripheral nerve (100%) and various other manifestations 35,36  
IgA 50% 
Vλ1 (#100%) 
Osteosclerotic bone lesions 
Unknown mechanism     
 Systemic capillary leak syndrome  IgG, IgA (rare) Systemic 45  
 TEMPI syndrome  IgG Systemic 46,47  
 Neutrophilic dermatosis  IgA >80% (except Sweet syndrome) Skin +++; different types and different associated manifestations 39  
 Acquired cutis laxa  Usually IgG; association with γ HCDD Skin +++Other manifestations (lung, digestive tract) 43  
 
 Scleromyxedema  IgG with slow electrophoretic mobility Skin +++; other localizations 40,41,52  
 Scleroedema  IgG Skin only 41  
 Schnitzler syndrome Acquired autoinflammatory syndrome by IL-1 deregulation? IgM Skin +++; systemic symptoms; osteosclerotic bone lesions 44  
 Sporadic late-onset nemaline myopathy   Exclusively muscles (skeletal and possibly cardiac) 48  

CAP, complement alternative pathway; CANOMAD, chronic ataxic neuropathy, ophthalmoplegia, monoclonal IgM protein, cold agglutinins, anti-disialosyl antibodies; HCDD, heavy-chain deposition disease; IL-1, interleukin 1; POEMS, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; TEMPI, telangiectasias, erythrocytosis with elevated erythropoietin level, monoclonal gammopathy, perinephric fluid collection, and intrapulmonary shunting.

*

Type II mixed cryoglobulinemia was observed in ∼10% of patients with chronic virus C infection.

Including pyoderma gangrenosum, Sweet syndrome, subcorneal pustular dermatosis, and erythema elevatum diutinum.

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