What is monoclonal gammopathy of clinical significance?

Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition, characterized by elevated levels of a monoclonal immunoglobulin (M-Ig) in the serum (< 30 g/L) but without any end-organ damage. Recently, the term monoclonal gammopathy of renal significance (MGRS) was introduced to describe several severe conditions that, similar to MGUS, emerge from the abnormal secretion of an M-Ig; unlike MGUS though, MGRS has a detrimental effect on renal function.

The primary cause of both MGUS and MGRS is the existence of a defective B-cell clone, which results in abnormal M-Ig secretion. Jean Paul Fermand from the Saint-Louis Hospital in Paris, France, and colleagues introduced a new term, monoclonal gammopathy of clinical significance (MGCS), to describe a set of pathologies derived from abnormally-functioning B-cell clones, and which lead to severe organ damage. The study was published in the journal Blood in July 2018. 

Key Data:

• MGCS mechanisms of tissue injury: Deposition of M-Ig; auto-antibody activity (auto-AbA); formation of immune complexes; complement activation; absorption of biologically active molecules; induction of cytokine secretion
• MGCS due to M-Ig deposition: Organized or non-organized deposits
• MGCS with organized M-Ig deposits:
  • AL amyloidosis: fibrillary deposits; systemic, mainly involved organs or tissues (MIO) = heart and kidney
  • Acquired Fanconi syndrome: precipitation of light chains (LC) into crystals; MIO = kidney
  • Crystal storing histiocytosis (CSH): M-Ig crystals within the lysosomes of macrophages; systemic
  • Crystalline keratopathy: M-Ig derived crystals in the cornea; MIO = cornea
  • Type I cryoglobulinemia: Microtubular or crystalline deposits; systemic
  • Immunotactoid glomerulopathy: Microtubular IgG deposits; MIO = kidney
• MGCS with non-organized deposits:
  • Monoclonal immunoglobulin deposition disease (MIDD): linear granular deposits along basal membranes; systemic, MIO = kidney
  • Proliferative glomerulonephritis with monoclonal Ig deposits (PGNMID): M-Ig deposited in the glomerular capillary walls and mesangium; limited to kidney
  • Macroglobulinosis: amorphous intra-dermis M-Ig deposits; limited to the skin (dermis)
• MGCS due to auto-AbA of M-Ig: activity against various antigens can cause organ lesions; antigens include: collagen IV, collagen VII, phospholipase A2 receptor; myelin-associated glycoprotein (MAG)
• Conditions due to Auto-AbA:
  • Bullous skin diseases: Auto-AbA against collagen VII; MIO = skin
  • IgM-associated peripheral neuropathy: Auto-AbA against MAG or less frequently gangliosides; MIO = peripheral nerve
  • Acquired C1 inhibitor deficiency: Auto-AbA of M-Ig resulting in angioedema
  • Von Willebrand disease: Auto-AbA of M-Ig resulting in bleeding
  • Cold agglutinin disease (CAD): Auto-AbA of M-IgM resulting in cold-induced skin manifestations and intra-vascular hemolysis
  • Type II mixed cryoglobulinemia: M-IgM with rheumatoid activity; MIO = skin, kidney, peripheral nerve
  • Xanthomatosis: Auto-AbA against various lipoproteins; MIO = skin, and tendons
• MGCS secondary to complement alternative pathway (CAP) activation
  • C3 glomerulopathy (C3G): Associated with an indolent M-IgG; MIO = kidney only
  • Atypical hemolytic uremic syndrome: Auto-AbA against CAP regulator protein, factor H; systemic
• MGCS due to cytokine secretion
  • POEMS: Marked elevation of serum VEGF levels which correlates with disease activity; MIO = Peripheral nerve
• MGCS of unknown mechanism
  • Scleromyxedema: MIO = skin
  • Scleredema: MIO = skin only
  • Acquired cutis laxa: MIO = mainly skin and other, such as lung and digestive tract
  • Schnitzler’s syndrome: MIO = mainly skin but also bone lesions and systemic symptoms
  • Systemic capillary leak syndrome: MIO = systemic
  • TEMPI syndrome: MIO = systemic
  • Sporadic late onset nemaline myopathy (SLONM): MIO = muscles only (skeletal and possibly cardiac)
• MGCS diagnosis:
  • For MGCS due to M-Ig deposition: It is important to show that the deposition is associated with pathological features; recommended laboratory techniques include immunohistology and electron microscopy
  • For MGCS due to auto-AbA of M-Ig: It is crucial to detect a higher titer of auto-AbA; recommended techniques include sensitive immuno-blotting or ELISA
  • For an MGCS secondary to CAP activation: It is recommended to measure the levels of the serum complement; low levels of protein components suggest activation of the complement classical pathway by immune-complexes
  • For MGCS of unknown mechanism: Epidemiological and immunological data may suggest a relationship between the symptoms and the condition
• MGCS treatment relies on limiting the activity of the small, abnormal B-cell clone. Effective treatments include monoclonal antibodies and local irradiation. Anti-CD38 monoclonal antibodies are currently being examined for the treatment of AL amyloidosis, and are likely to be used in the treatment of various MGCS. High-dose intravenous immunoglobulins (IVIG) are sometimes proposed as an alternative, but their efficacy is usually temporary.

Conclusions

The term MGCS can be used to encompass a series of monoclonal gammopathies that share as common feature abnormal levels of an M-Ig and whose origin lies on a defective B-cell clone. Uncontrolled proliferation of this clone may lead to deleterious defects and severe organ damage; thus, identifying and treating these conditions early, can help limit their pathogenic consequences.