IgA Monoclonal Gammopathy Research Articles

Le syndrome POEMS (ou syndrome de Crow-Fukase)

POEMS is an acronym for polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes. POEMS syndrome is also called Crow-Fukase syndrome, chiefly in Japan. The 5 above mentioned features are not always present at the first examination. The minimal criteria to establish the diagnosis are the presence of a demyelinating and axonal polyneuropathy associated with an IgA or IgG monoclonal gammopathy, the light chain being almost always lambda, and at least 2 of the 8 other features: sclerosing plasmocytoma, endocrinopathy, skin changes, organomegaly, Castleman's disease, anasarca, papillary edema or thrombocytosis. Among these features, only cutaneous glomeruloid angioma are specific. Ultrastructural identification of uncompacted myelin lamellae on the peripheral nerve biopsy is also a strong argument in favor of the diagnosis. An associated "osteosclerotic" bone lesion must be carefully searched, because its treatment may improve the other features of the syndrome, especially the neuropathy. Cytokines and the vascular growth endothelial factor might play a role in the pathogenesis of this rare multisystemic disorder.

Monoclonal gammopathies of undetermined significance: a review.

Monoclonal gammopathy of undetermined significance (MGUS) denotes the presence of a monoclonal protein (M-protein) in patients without evidence of multiple myeloma (MM), macroglobulinemia, amyloidosis (AL), or a related plasma cell proliferative disorder. MGUS is found in approximately 3% of persons older than 70 years and in about 1% of those older than 50 years. In a series of 1384 patients from south-eastern Minnesota in whom MGUS was diagnosed at Mayo Clinic from 1960 through 1994, the risk of progression was 1% per year. Patients were at risk of progression even after 25 years or more of a stable monoclonal gammopathy. The risk of development of MM was increased by 25-fold, the risk of macroglobulinemia was 46-fold, and the risk of primary AL was 8.4-fold when compared with a similar population (Surveillance, Epidemiology and End Results). The concentration of the serum M-protein was the major independent predictor of progression. Patients with an immunoglobulin M (IgM) or an IgA monoclonal gammopathy had a higher risk of progression than those with an IgG monoclonal gammopathy. The presence of a urine M-protein or the reduction of one or more uninvolved Igs was not a risk factor for progression. MGUS may be associated with many different disorders, including lymphoproliferative diseases, leukemia, connective tissue disorders, dermatologic diseases, and neurologic disorders.

Immunopathogenetic Role Of The M‐Protein In Neuropathy Associated With IgA Monoclonal Gammopathy

Neuropathy has been reported in some patients with IgA monoclonal gammopathy of undetermined significance (MGUS) but the clinical and pathogenetic relevance of this association remains unclear. This is because the clinical and electrophysiological features of the neuropathy in reported patients were quite heterogeneous and only occasionally endoneurial deposits or anti‐neural reactivity of IgA M‐proteins were found. In order to clarify the possible role of IgA M‐proteins in the neuropathy we studied their reactivity with nerve antigens in 12 patients with neuropathy associated with IgA MGUS and in 15 patients with IgA MGUS without clinical or electrophysiological evidence of neuropathy. Patients' sera were tested for IgA reactivity with the glycolipids GM1, GM2, GD1a, GD1b, GQ1b and sulfatides by ELISA and with central (CNS) and peripheral nervous system (PNS) myelin and whole nerve homogenates by Western Blot. No IgA reactivity with any of the gangliosides tested or sulfatide was detected by ELISA in patients with neuropathy and IgA MGUS. By Western blot only one neuropathy patient had an intense IgA reactivity with several protein bands of the molecular weight (MW) of 80 to 200 kD, including high MW neurofilaments. A similar though less intense IgA reactivity with the same bands was detected in one patient without neuropathy. No other reactivity with neural proteins was detected in patients' sera more frequently or more intensely than in controls. The clinical features of the neuropathy in the four patients whose clinical reports were available showed an usually mild, predominantly motor (2) or sensory (1) or mixed (1) impairment, while electrophysiological studies showed a predominant axonal (2), demyelinating (1) or mixed (1) neuropathy. In the only patient in whom sural nerve biopsy was performed no endoneurial deposits of IgA were found. The heterogeneity of the clinical and electrophysiological findings in these patients together with the lack of a consistent pattern of IgA reactivity with neural antigens in the 12 patients examined fail to support, at least in these patients, a possible immunopathogenetic role of the IgA M‐proteins in the neuropathy.

An Unusual Association of Monoclonal Gammopathy, Paroxysmal Nocturnal Haemoglobinuria and Myelodysplastic Syndrome Transformed into Acute Myeloid Leukaemia: Coexistence of Triple Clonal Disorders

An unusual association of paroxysmal nocturnal haemoglobinuria (PNH), myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML) and monoclonal gammopathy is reported. A 60–year old male, who had a history of IgA monoclonal gammopathy, presented with haemoglobinuria and colic pain. Flow cytometry showed CD55negative/59dim peripheral red cells, and bone marrow examination disclosed MDS. Eleven months, he developed later AML with disappearance of the PNH clones, although the monoclonal gammopathy persisted. The relationship between PNH and MDS has not fully been assessed, although our findings indicate that these triple clonal disorders, all coexisted in one patient.

Myelin widenings and MGUS-IgA: An immunoelectron microscopic study

A few studies have reported a variety of nonspecific histological lesions in patients with IgA monoclonal gammopathies and polyneuropathy. In our case, using electron microscopy, we observed widenings of the myelin lamellae identical to those commonly described in IgM neuropathies with anti-myelin-associated glycoprotein activity. Using immunoelectron microscopy, we demonstrated a direct involvement of IgA in myelin lesions. The search for a direct link between monoclonal dysglobulinemia, regardless of type, and polyneuropathy is important and may influence treatment.

False-Positive Reactions for IgA Anti-Phospholipid and Anti-β2-Glycoprotein I Antibodies in Patients with IgA Monoclonal Gammopathy

We report here that measurements of IgA anti-cardiolipin (aCL) and anti-β2-glycoprotein I (β2GPI) antibodies are unreliable in patients with IgA monoclonal gammopathies (MGs). MGs are characterized by monoclonal immunoglobulins produced by a proliferating B-lymphocyte clone. Monoclonal gammopathy of undetermined significance (MGUS) is the most common type of MG (1); the monoclonal component (MC) is IgA in 15–25% of MGs (2). aCL antibodies, originally described in patients with systemic lupus erythematosus (3), have been detected in patients with other autoimmune diseases (4)(5) and in the antiphospholipid syndrome (6)(7) as well as in nonrheumatologic disorders (8) and in healthy individuals (9)(10)(11). In patients with connective tissue diseases and antiphospholipid syndrome, aCL antibodies are most frequently IgG, followed by IgM. Kalunian et al. (12), however, reported a high incidence of IgA, rather than IgG-aCL antibodies associated with thrombosis and fetal loss, and other reports have suggested that IgA-aCL antibodies may have a clinical meaning even in the absence of IgG- or IgM-aCL (13)(14)(15)(16)(17)(18)(19)(20)(21). Their prevalence in healthy subjects seems negligible; in a series of 389 healthy pregnant women, Lynch et al. (22) found only one positive case (0.3%). Therefore, to properly assess the risk of thrombosis, thrombocytopenia, and recurrent abortions in systemic lupus erythematosus patients, the determination of IgA-aCL antibodies has been recommended (18)(21). Very recently, the same recommendation was also made for anti-β2GPI antibody determination because anti-β2GPI restricted to the IgA isotype can be found in the sera of systemic lupus erythematosus patients with thrombosis (23). IgG- or IgM-aCL activity has been described occasionally in subjects with MG (24)(25)(26)(27), but …

IgA .ALPHA.1.LAMBDA.1 molecule detected by non-reducing urea-SDS-PAGE in monoclonal IgA gammopathy patient with albuminuria.

Abnormal IgA molecule, which lacked in disulfide bridges between α chains, was detected from the sera of patients of monoclonal IgA gammopathy with albuminuria by the method of urea-SDS-PAGE performed in the reducing-agent-free condition. Throughout the procedure, protein in the specimen was kept away from any reducing agent to avoid an artificial production of half molecules during the experiment. A band of 80kDa protein, which showed immunoreactivity to both anti-α- and anti-λ-chain antibodies, was detected in sera from four patients of monoclonal IgA gammopathy accompanied with albuminuria. The molecular mass and the immunoreactivity indicated that the 80kDa protein was so-called“IgA half molecule”(α1λ1). The band of α1λ1 molecule was faint on the gel in the specimens from patients of no albuminuria. The abnormal α1λ1 molecule was eluted from the column of gel permeation chromatography into fractions corresponding to 320kDa when it was performed using urea-free buffer. The chromatographic behavior suggested the non-covalent interaction between the abnormal α1λ1 molecules in the non-denaturing buffer condition.

Subcorneal pustular dermatosis in a patient with aplastic anemia

Subcorneal pustular dermatosis (SPD) is a chronic, relapsing vesiculopustular eruption that typically affects the trunk and intertriginous areas and usually occurs in women more than 40 years of age. 1 Sneddon IB Wilkinson DS. Subcorneal pustular dermatosis. Br J Dermatol. 1979; 100: 61-68 Crossref PubMed Scopus (104) Google Scholar We describe a case of SPD in a patient with aplastic anemia induced by antituberculosis medications. Although the association of SPD with paraproteinemia, myeloma, and inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease has been recognized, 2 Kasha EE Epinette WW. Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) in association with a monoclonal IgA gammopathy: a report and review of the literature. J Am Acad Dermatol. 1988; 19: 854-858 Abstract Full Text PDF PubMed Scopus (83) Google Scholar , 3 Delaporte E Colombel JF Nguyen-Mailfer C et al. Subcorneal pustular dermatosis in a patient with Crohn’s disease. Acta Derm Venereol (Stockh). 1992; 72: 301-302 PubMed Google Scholar an association with aplastic anemia has not been previously reported.

Multiple antibodies to nerve glycoconjugates in a patient with neuropathy and monoclonal IgA gammopathy

Several immunological abnormalities were found in a patient with mixed axonal and demyelinating neuropathy in association with a prominent monoclonal IgA A band in his serum. He had antibodies to the major LM1 ganglioside of human nerve that were restricted to the IgA class, but they were polyclonal arid distinct from the major monoclonal IgA component. He also had a low level of a monoclonal IgMλ antibody to the myelin-associated glycoprotein and sulfate-3-glucuronyl paragloboside that was not detected by routine immunofixation. The observations made on this complex patient, are presented in the context of emphasizing that immunological reactivities to neural antigens; that are not due to the principal monoclonal antibody may be present in patients with neuropathy in association with gammopathy.

Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies.

Approximately 10% of patients with peripheral neuropathy of otherwise unknown etiology have an associated monoclonal gammopathy. Both the neuropathies and the monoclonal gammopathies in these patients are heterogeneous, but several distinct clinical syndromes that may respond to specific therapies can be recognized. It is important to recognize these syndromes because monoclonal gammopathies also occur in 1% of the normal adult population, and in some cases, monoclonal gammopathies are coincidental and unrelated to the neuropathy. In patients with IgM monoclonal gammopathies, IgM M proteins frequently have autoantibody activity and are implicated in the pathogenesis of the neuropathy. IgM M proteins that bind to myelin-associated glycoprotein (MAG) have been shown to cause demyelinating peripheral neuropathy; anti-GM1 antibody activity is associated with predominantly motor neuropathy, and anti-sulfatide or chondroitin sulfate antibodies are associated with sensory neuropathy. The IgM monoclonal gammopathies may be malignant or nonmalignant, and polyclonal antibodies with the same specificities are associated with similar clinical presentations in the absence of monoclonal gammopathy. IgG or IgA monoclonal gammopathies are associated with neuropathy in patients with osteosclerotic myeloma or the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy myeloma, and skin changes). Amyloidosis or cryoglobulinemic neuropathies can occur with either IgM or IgG and IgA monoclonal gammopathies. Therapeutic intervention depends on the specific clinical syndrome but is generally directed at removing the autoantibodies, reducing the number of monoclonal B cells, and interfering with the effector mechanisms.

Atypical pemphigus associated with monoclonal IgA gammopathy

We describe a 60-year-old woman with atypical pemphigus and IgA-λ monoclonal gammopathy. Histopathologic study of vesiculopustular lesions showed intraepidermal acantholytic and neutrophilic blisters. Direct immunofluorescence revealed intercellular IgG deposition with concurrent deposits of IgA and C3. Indirect immunofluorescence and immunoblotting studies revealed that the patient had circulating IgG anti-intercellular antibodies that recognized the 150 kd desmoglein (pemphigus foliaceus antigen) in bovine desmosome preparation. Immunoblot studies with human epidermal extract showed that the IgG of this patient exclusively reacted with the 140 kd protein (between the 150 kd human desmoglein and the 130 kd human pemphigus vulgaris antigen), the nature of which is currently unknown. The patient also had IgA anti-intercellular autoantibodies, which reacted with the desmoglein in the bovine desmosome sample but did not show any reactivity in human epidermal extract.

Subcorneal Pustular Dermatosis in a Patient with Hyperthyroidism

A case of subcorneal pustular dermatosis (SPD) is reported in a 48-year-old man with a 2-year history of hyperthyroidism (Graves' disease). SPD has been reported in association with IgA monoclonal gammopathy, but to our knowledge it has not been associated with hyperthyroidism. The coexistence of hyperthyroidism and SPD suggests that immunologic factors may play a role in the pathogenesis of SPD.

Erythema elevatum diutinum

Erythema elevatum diutinum can be thought of as a rare presentation of chronic cutaneous vasculitis. Although the exact pathogenesis is unknown, it has been associated with a wide range of clinical illnesses including IgA monoclonal gammopathy, myelodysplastic syndrome, rheumatoid arthritis, inflammatory bowel disease, streptococcal infection, and HIV. Lesions typically present as asymptomatic, red-brown papules and nodules symmetrically distributed with a predilection for skin overlying joints, buttocks, and the Achilles tendon. Dapsone is considered first-line treatment.

Polyneuropathy associated with IgA monoclonal gammopathy of undetermined significance

Although polyneuropathies associated with IgM and IgG monoclonal gammopathies have been well described, polyneuropathy with IgA monoclonal gammopathy of undetermined significance (MGUS) is less commonly seen and has not been well studied. We reviewed the clinical and electrodiagnostic features of 5 such patients, and the sural nerve biopsy findings in 4 of them. One patient was diabetic, while 4 were free of other diagnoses commonly associated with neuropathy. Clinical presentations were varied. Electrodiagnostic and histological studies ranged from primary demyelination to primary axon loss to a mixed axonal/demyelinating picture. Three patients who were treated appeared to respond to prednisone or intravenous gamma globulin, despite clear clinical, electrodiagnostic, and histological differences. We conclude that the polyneuropathy associated with IgA MGUS is heterogeneous, similar to that in IgM and IgG MGUS. A trial of immunomodulating therapy appears to be warranted in such patients if the neuropathy is sufficiently severe.

Intraepidermal IgA pustulosis

Since 1979, 29 patients with intraepidermal IgA detected by direct immunofluorescence have been reported. A review shows that they have a cutaneous disease clinically similar to subcorneal pustular dermatosis, or Sneddon-Wilkinson disease. The pustules may be subcorneal or intraepidermal. IgA deposits are usually found on the intercellular substance of the epidermis, although a subcorneal linear pattern has also been described. Circulating IgA class antiepidermal autoantibodies may be present. The disease usually responds to dapsone. In six cases, a monoclonal IgA gammopathy was present. Although little is known about the pathogenesis of this condition, we believe that it represents a distinct entity among the group of the neutrophilic dermatoses. Various diagnostic terms have been used; we propose intraepidermal IgA pustulosis.

Erythema elevatum diutinum: A clinical and histopathologic study of 13 patients

Erythema elevatum diutinum is a rare condition representing a chronic leukocytoclastic vasculitis. Clinical and laboratory features of the disease were reviewed to better understand the disease. The medical records and histopathologic slides of 13 patients with erythema elevatum diutinum were studied. The lesions were violaceous, deep red, or brown and typically were papules or plaques. Lesions were most often located on the extensor surfaces of the extremities. Associated medical problems included hematologic abnormalities in six patients: IgA clonal gammopathies (four), multiple myeloma (one), and myelodysplasia (one). Erythema elevatum diutinum preceded the myeloproliferative disorders by an average of 7.8 years. All patients showed vasculitis. Leukocytoclasia was present in 27 of 35 specimens. The predominant cell type in the inflammatory infiltrate was polymorphonuclear leukocytes or a mixture of polymorphonuclear leukocytes and lymphocytes. The most significant finding of this study is the association of erythema elevatum diutinum with hematologic disease, most frequently an IgA monoclonal gammopathy.

Polyneuropathy associated with IgA monoclonal gammopathy: a hypothesis of its pathogenesis

We describe three patients with chronic progressive polyneuropathy associated with IgA monoclonal gammopathy. Two patients had a prominent sensory neuropathy and one had a prominent motor neuropathy. Sural nerve biopsies showed axonal degeneration in all cases. In immunocytochemical studies patients' IgG immunostained axons. By Western immunoblot a band of IgG reactivity with an axonal protein of 66 kDa was found. No band of IgA and IgM were found. We suggest the possibility that the IgA monoclonal protein may act as a stimulating factor of preexisting B cell clones eliciting an immune reaction against nerve antigens.

Pyoderma Gangrenosum With Pulmonary Involvement

A 60-year-old woman had a typical pyoderma gangrenosum with monoclonal IgA gammopathy and atrophic gastritis. Two years after the onset of her skin disease, she had evidence of pulmonary abscesslike involvement. Corticosteroid therapy led to healing of skin and lung diseases. This case stresses the multisystemic manifestations of neutrophilic dermatoses with special attention to pulmonary involvement.

Monoclonal gammopathies in children

Over a 10-year period sera of 4000 pediatric patients were subjected to agar gel electrophoresis and immunoelectrophoresis. Retrospective examination of the electrophoresis patterns indicated that single or multiple homogeneous immunoglobulin components were present in sera of 155 children (3.9%). They were most frequently found in patients suffering from primary and secondary immunodeficiency diseases, hematological malignancies, autoimmune diseases, and severe aplastic anemia. Follow-up analysis revealed that most of these monoclonal gammopathies were transient. The monoclonal gammopathies in the serum of 79 patients were identified by immunoblotting for class and light-chain isotypes. A marked absence of IgA monoclonal gammopathies and a predominance of monoclonal gammopathies of the lambda light-chain isotype were found. Most of the B-cell mono- or oligoclonal proliferations in children can probably develop due to a disturbance in the regulatory T-cell function.

A case of diffuse panbronchiolitis(DPB) with benign monoclonal IgA gammopathy and IgA nephropathy with monoclonal IgA deposition.

A case of diffuse panbronchiolitis (DPB), associated with benign monoclonal IgA gammopathy and IgA nephropathy is described. The IgA deposition in the glomeruli of the patient was identified as consisting mainly of the monoclonal IgA having the same idiotype as that of serum monoclonal IgA. Recurrent infections of Hemophilus influenzae and Pseudomonas aeruginosa in the respiratory tract might have enhanced IgA-mediated immunity at the mucosal surface of the bronchiole, and ultimately induced monoclonal IgA gammopathy and IgA nephropathy.