Inflammation: it is an integral part of the body’s natural response to harmful stimuli, but too much of it and the body itself can suffer damage. So as physicians we must determine how to manage it and when to intervene.

How do we tweak the immune system so that it functions normally when foreign pathogens are detected, but does not turn on the body by mistake, as it does in the case of autoimmune disorders? It is a question as old as medicine itself, and today, with a number of autoimmune diseases identified and under investigation, it is as urgent as it was thousands of years ago. 

Chalayer and colleagues have written a brilliant study, comparing the roles of fragment crystallizable receptors in autoimmune and inflammatory disease. “Antibodies are central mediators of the antimicrobial immunological defense, but when autoreactive, they can become deleterious and be functionally involved in the pathogenesis of various autoimmune and inflammatory disorders,” they wrote. 


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The researchers provided a list of autoimmune diseases that involve an aberrant inflammatory pathway, including rheumatoid arthritis, systemic lupus erythematosus, Crohn disease, and autoimmune hemolytic anemia (AIHA). In this article, we will be focusing on inflammation and AIHA, of which cold agglutinin disease (CAD) is a subtype. 

Understanding AIHA and CAD

At a glance, AIHA may seem like a simple autoimmune disease in which autoantibodies are directed to destroy red blood cells, thus causing anemia. However, it has always been a clinically heterogeneous disease, with patients suffering from mild to severe anemia. “It is now known that this is due to variations in autoantibodies’ thermal amplitude, isotype and ability to induce complement cascade activation, as well as to different bone marrow capacity to compensate,” Chalayer et al wrote. 

Warm AIHA constitutes about 60% to 70% of all forms of AIHA. What sets it apart is that “warm AIHA has been associated with an increased risk for thromboembolism, whereas classical risk factors are frequently absent in these patients,” Chalayer et al wrote. “Hemolysis by itself is likely to be an independent risk factor for thrombosis, as this increased risk for thrombosis is present in multiple hemolytic diseases, but other specific mechanisms are certainly involved.” 

What about cold AIHA? We turn to the work of Sigbjørn Berentsen, MD, PhD, an expert on AIHA, who wrote, “Cold-antibody [AIHAs] are mediated by autoantibodies characterized by a temperature optimum of the antigen-antibody (AgAb) reaction at 0oC-4oC.” In cold AIHA, which accounts for about 25%-30% of AIHAs, cold agglutinins bind to red blood cell antigens at low temperatures, causing them to agglutinate. 

Read more about CAD etiology 

And how do cold agglutinins factor into CAD? The AIHA consensus document defines CAD as “an AIHA characterized by a monospecific direct antiglobulin test (DAT) strongly positive for complement fragment C3d and a cold agglutinin titer of 64 or higher at 4°C.

”DAT for IgG is usually negative, but can be weakly positive in up to 20% of the patients. There may be occasional cases with a cold agglutinin titer <64,” Dr. Berentsen wrote. 

Cold agglutinin syndrome is further defined by “the presence of an associated clinical disease, for example, infection, autoimmune disorder, overt evidence of a lymphoma (clinical or radiological), or other malignancy,” Dr. Berentsen wrote. “Typical underlying infections are Mycoplasma pneumoniae pneumonia, Epstein Barr virus (EBV) infection, or, rarely, other specific infections.” 

Treatment Recommendations

Jäger et al, in their landmark study on the recommendations for treating AIHA from the First International Consensus Meeting, provided clear and concise indications for therapy in both warm and cold AIHA. With regards to cold AIHA, they wrote, “Treatment would usually not be recommended for patients whose Hb is >10 g/dL. Exceptions could be made for patients with significant comorbidities such as ischemic cardiomyopathy and chronic obstructive pulmonary disease that would reduce oxygen delivery to the tissues unrelated to the oxygen-carrying capacity of the blood.”

The research team wrote—in no uncertain terms—that the goal of treatment is to increase hemoglobin levels in symptomatic anemia. Obviously, this might entail blood transfusions. 

As for the first-line treatment for CAD, Jäger and colleagues wrote, “Rituximab, alone or in combination with bendamustine, is the best documented first-line treatment. Rituximab can be repeated as monotherapy or in combination with bendamustine or fludarabine as second line treatment. Bortezomib has also shown efficacy.” 

Read more about CAD treatment 

In cases of severe/life-threatening hemolysis and anemia, also known as acute exacerbations of AIHA, blood transfusions should be given according to the patient’s hemoglobin levels, preferably with a blood warmer. Eculizumab is a drug that is ideal for blocking the terminal complement pathway, as well as intravascular hemolysis. 

From the pathophysiology to the treatment of AIHA, inflammation features front and center. AIHA, and indeed all autoimmune diseases, can be likened to an army that attacks its own country. To extend this analogy, the challenge here is to rewire the army so that it protects instead of destroys. It is no easy task, but it is one that countless medical researchers around the world are pursuing. 

References

Berentsen S. New insights in the pathogenesis and therapy of cold agglutinin-mediated autoimmune hemolytic anemia. Front Immunol. 2020;11:590. doi: 10.3389/fimmu.2020.00590

Chalayer E, Gramont B, Zekre F, et al. Fc receptors gone wrong: A comprehensive review of their roles in autoimmune and inflammatory diseases. Autoimmun Rev. Published online December 14, 2021. doi:10.1016/j.autrev.2021.103016

Jäger U, Barcellini W, Broome CM, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting. Blood Rev. 2020;41:100648. doi:10.1016/j.blre.2019.100648