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
| . | Mechanism . | Main characteristics of monoclonal gammopathy . | Main organ(s) involved . | Reference . |
|---|---|---|---|---|
| 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 |
| . | Mechanism . | Main characteristics of monoclonal gammopathy . | Main organ(s) involved . | Reference . |
|---|---|---|---|---|
| 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.