User:It's gonna be awesome/Primary chronic cold agglutinin disease

Primary chronic cold agglutinin or Chronic cold agglutinin disease (CAD) and Primary cold agglutinin disease is a subgroup of cold agglutinin disease which is a nether of autoimmune hemolytic anemia. Primary CAD has traditionally been defined by the absence of any underlying or associated disease. In a Norwegian population-based study, the prevalence of CAD was 16 per million and the incidence was about 1 per million per year, making CAD account for approximately 15% of AIHA. In general, monoclonal CA are more pathogenic than polyclonal CA and hexameric IgM is more pathogenic than pentameric IgM. It has been known for decades that, in patients with CAD, IgM-antibodies with CA-activity are monoclonal and, in more than 90% of the patients, show κ light chain restriction. .

Classification

 * Autoimmune hemolytic anemia.


 * Warm-antibody type
 * Primary
 * Secondary
 * Cold-antibody type
 * Primary chronic cold agglutinin disease
 * Secondary cold agglutinin syndrome
 * Associated with malignant disease
 * Acute, infection-associated (acute cold antibody mediated AIHA complicating Mycoplasma pneumoniae or viral infections )
 * Paroxysmal cold hemoglobinuria
 * Mixed cold- and warm-antibody type

Pathophysiology
CAD patients must have a clonal B-cell lymphoproliferative disorder which has not been fully elucidated until the last years. Two large, retrospective studies of consecutive patients with primary CAD found signs of a bone marrow clonal lymphoproliferation in most patients, but in both series the individual hematological and histological diagnoses showed a striking heterogeneity. In one of the series, lymphoplasmacytic lymphoma (LPL) was the most frequent finding, while marginal zone lymphoma (MZL), unclassified clonal lymphoproliferation, and reactive lymphocytosis were also frequently reported. The explanation for this perceived heterogeneity was probably revealed by a recent study in which bone marrow biopsy samples and aspirates from 54 patients with CAD were systematically reexamined by a group of lymphoma pathologists, using a standardized panel of morphological, immunohistochemical, flow cytometric, and molecular methods. . The bone marrow findings in these patients were consistent with a surprisingly homogeneous disorder termed “primary CA-associated lymphoproliferative disease” by the authors and distinct from LPL, MZL, and other previously recognized lymphoma entities. The MYD88 L265P somatic mutation, typical for LPL, could not be detected in the samples from patients with CAD.

Mechanisms of Erythrocyte Destruction


CA are usually directed against the Ii blood group system, most CA in CAD being specific for the I carbohydrate antigen. Cooling of blood during passage through acral parts of the circulation allows CA to bind to RBC and cause agglutination (Figure 3). Being a strong complement activator, antigen-bound IgM-CA on the cell surface binds C1 and thereby initiates the classical complement pathway. C1 esterase activates C4 and C2, generating C3 convertase, which results in the cleavage of C3 to C3a and C3b. Upon returning to central parts of the body with a temperature of 37°C, IgM-CA detaches from the cell surface, allowing agglutinated erythrocytes to separate from each other, while C3b remains bound. A proportion of the C3b-coated RBCs is sequestered by macrophages of the reticuloendothelial system, mainly Kupfer cells in the liver. On the surface of the surviving RBCs, C3b is cleaved, leaving high numbers of C3d molecules on the cell surface. These mechanisms explain why the monospecific DAT is strongly positive for C3d in patients with CA-mediated hemolysis and, in the majority, negative for IgM and IgG.

Complement activation may proceed beyond the C3b formation step, resulting in C5 activation, formation of the membrane attack complex (MAC), and intravascular hemolysis. Due to surface-bound regulatory proteins such as CD55 and CD59, however, the complement activation is usually not sufficient to produce clinically significant activation of the terminal complement pathway. The major mechanism of hemolysis in stable disease, therefore, is the extravascular destruction of C3b-coated erythrocytes. Obviously, however, C5-mediated intravascular hemolysis does occur in severe acute exacerbations and in some profoundly hemolytic patients, as evidenced by the finding of hemoglobinuria in 15% of the patients and the observation of a beneficial effect of C5 inhibition in at least occasional patients. Febrile infections, major trauma, or major surgery can result in acute exacerbation of hemolytic anemia in at least two-thirds of patients with CAD. The explanation for this paradoxical exacerbation is that, during steady-state chronic disease, most patients are complement-depleted with low levels of C3 and often undetectable levels of C4. During acute phase reactions, C3 and C4 are repleted and exacerbation of complement-induced hemolysis ensues.

Management
In textbooks and review articles, it is often postulated that typical patients with CAD are just slightly anemic and do not need pharmacological therapy. This holds true for a minority only; the median hemoglobin level in affected individuals is 9.0 g/dL and the lower tertile is 8.0 g/dL. Furthermore, at least 90% of the patients experience cold-induced circulatory symptoms caused by RBC agglutination, most often in the form of acrocyanosis and/or Reynaud's phenomenon that can range from slight to disabling. In many patients, therefore, CAD is not an indolent disease in terms of major clinical symptoms and quality of life. In Norway as well as the United States, drug therapy had been attempted in 70–80% of unselected patients studied in two relatively large retrospective series In contrast to W-AIHA, corticosteroids and other unspecific immunosuppressive drugs are of little or no value in CAD.

The relative success in therapy for CAD during the last 10–12 years has been achieved by targeting the pathogenic B-cell clone. Rituximab monotherapy has been shown in prospective studies to induce remission in approximately half of the patients, although complete remissions are unusual and the median response duration is only about 1 year. In both studies, events of cytokine-related reactions to rituximab were few and readily treatable. The studies found no significant problems with infectious complications due to the induced B-cell lymphopenia and hypogammaglobulinemia   Data from rituximab maintenance in follicular lymphoma indicate that, in adults, even prolonged or repeated administration is safe with regard to infections. Very rare cases of progressive multi-focal leukoencephalopathy and hepatitis B reactivation have been reported, however, in patients receiving rituximab for polyclonal autoimmune disorders. Any causal associations are uncertain because of concomitant immunosuppressive therapies and immune dysregulation as part of the autoimmune disease itself.

Prognosis
In a more recent prospective trial, combined therapy with rituximab and fludarabine produced very high response rates (remission in 75% of the patients, including 20% complete remissions) and the median response duration was more than 66 months. This regimen was, however, found to be significantly more toxic than rituximab monotherapy. No other immunochemotherapy regimens have been studied in published clinical trials. According to single case reports, favorable outcome has been observed following bortezomib-based regimens and rituximab-bendamustine combination therapy.

Transfusion can safely be given in CAD provided specific precautions are undertaken, although these precautions are entirely different from those required in W-AIHA. Such requirements have been extensively described elsewhere.

Free PMC articles (For self-reminding)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409172/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326213/

https://www.ncbi.nlm.nih.gov/pmc/?term=primary+cold+agglutinin+disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4396542/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6129358/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096571/

External links (Self-reminding only)
Basic overview:


 * https://rarediseases.org/rare-diseases/anemia-hemolytic-cold-antibody/
 * https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=56425

Reference
Category:Cold autoimmune hemolytic anemia