Pure red cell aplasia is a rare blood disorder that is distinguished by normocytic/normochromic anaemia as well as severe reticulocytopenia. This disease can occur due to two different circumstances, as a primary autoimmune disorder or secondary to another medical condition. This article will provide more information regarding pure red cell aplasia, the current first-line immunosuppressive therapies, and the current research on potential new immunosuppressive therapies for pure red cell aplasia.

What is pure red cell aplasia?

Pure red cell aplasia is a rare anaemia disorder which is characterized by anaemia with red blood cells that are normal in size and colour known as normocytic/normochromic anaemia. In addition, severe reticulocytopenia which is an abnormal decrease in circulating red blood precursors known as reticulocytes and the lack of or scarcity of the developing cells in the bone marrow known as erythroid precursors.¹ Diamond-Blackfan anaemia is a type of anaemia that is at times classified as a type of pure red cell aplasia which is found to be present at birth known as congenital pure red cell aplasia. It should be noted that there is a distinction between acquired pure red cell aplasia which manifests after birth and congenital pure red cell aplasia. These distinctions include the presence of macrocytic anaemia (this is a condition in which there are many large red blood cells and fewer normal-sized red blood cells), growth and developmental abnormalities, and mutations in some proteins.² 

Clinical manifestations of pure red blood cell aplasia

Acquired pure red cell aplasia is mostly found in adults, however, sometimes it is also found in children.³ This form of pure red cell aplasia can be a primary disorder which is a medical condition that is not a result of another underlying condition and exists independently or a secondary disorder which occurs as a consequence of another medical condition. Primary pure red cell aplasia is an autoimmune disorder resulting from immunoglobulin G inhibitors which are antibodies targeting and suppressing the development of red blood cells (erythropoiesis).⁴ Additionally, primary pure red cell aplasia can develop from clonal disorder wherein genetic mutations occur after birth in the precursors of red blood cells. This clonal disorder resembles myelodysplastic syndrome, a rare type of blood cancer.^1,5,6 Secondary pure red blood cell aplasia, on the other hand, has been linked to a large range of inflammatory/autoimmune, cancerous, infectious disorder, or side effects of different drugs.^1,7 Studies have shown that only rifampicin (an antibiotic) and diphenylhydantoin (an anti-seizure medication) are associated with the induction of immunoglobulin G inhibition.^8,9,10,11 Pure red cell aplasia has been associated with pregnancy, however, this is very uncommon and is believed to be due to the immune system attacking the body.¹² 

Diagnostic Methods for pure red cell aplasia

Pure red blood aplasia is suspected when an individual has normocytic/normochromic anaemia in isolation with severe reticulocytopenia. This means, that although red blood cells (erythrocytes) are normal in size and colour, the number of red blood cell precursor cells (reticulocytes) from which mature erythrocytes develop, is drastically decreased.  In the past, reticulocytopenia was diagnosed by manually counting reticulocytes andIt was found that a reticulocyte count of less than 10,000/μL is associated with a deficit.^1,13 However, In pure red blood cell aplasia, white blood cells (leukocytes, the immune cells of our body) and platelets (cells that prevent and stop bleeding - a natural blood coagulant) were found to have normal characteristics. abnormalities of those cells is associated with coexisting diseases, for example, chronic lymphocytic leukaemia, a rare blood cancer that affects the bone marrow and blood.^11,14 Ultimately, pure red cell aplasia is diagnosed through changes in the physical characteristics, appearance, and structure of cells within bone marrow.¹¹ Once pure red cell aplasia has been diagnosed, subsets need to be identified as they may require specific treatments and can help with determining the potential outcomes or predictions of the disorder.¹⁵ 

Immunosuppressive Therapy 

T lymphocytes, also known as T cells, are a type of white blood cell which plays a key role in the development and progression of pure red cell aplasia. Taking this into consideration, current therapy is directed at these cells in the form of immunosuppressive therapy.¹⁶ Immunosuppressive therapy is a type of treatment that weakens or suppresses the activity of the immune system. The treatments used include the following;

• Cyclosporine A: cyclosporine A, also spelt as ciclosporin, inhibits the production and release of T cells. It can be given as an oral solution or capsule as well as an infusion. The common side effects include diarrhoea, vomiting, fatigue, decreased appetite, electrolyte imbalance, headaches, fevers, hair changes, skin reactions, seizures, or tremors.¹⁷ At present, it is the most effective first-line treatment which has a response rate that remains around 70-75% consistently.¹⁶ First-line treatments are the primary course of treatment used by doctors for a certain disease. This drug can also be administered alongside corticosteroids, this regime has been shown to have a more favourable response rate. Nonetheless, one-quarter of patients may require an alternative treatment as they do not respond to the drug. In addition, some groups of patients cannot tolerate the treatment such as those with renal failure which occurs when the kidney cannot function properly.¹⁷ 
• Corticosteroids: corticosteroids also known as steroids are anti-inflammatory drugs and can decrease immune system activity. Corticosteroids can come in many different formulations which include tablets, injections and solutions. The side effects include mood changes, insomnia (difficulty sleeping), and increased appetite.¹⁹ When used alone as a first-line therapy corticosteroids have a response rate of 39%.¹⁶ 
• Rituximab: Rituximab is a monoclonal antibody which are antibody created in labs. This drug takes 2-6 weeks to take effect. The side effects include tiredness, sickness, breathing difficulties, itching of the skin, runny nose, back pain, flushing and irregular heart rate.²⁰ This treatment has response rates of 62%.¹⁶ It should be noted that this course of treatment is mostly used for a specific subtype of pure red blood cell aplasia which is associated with lymphoproliferative disorders.²¹ Lymphoproliferative disorders are a diverse group of diseases which is distinguished by uncontrolled lymphocyte production.²² 
• Antithymocyte globulin: Antithymocyte globulin are antibodies which are developed through injecting human T cells into horses, the horses produce antibodies. the antibodies are then collected and purified to create antithymocyte globulin medication. This process does not harm the animals involved. The treatment generally requires up to 3 weeks of hospitalization. It is administered through a central line which is a thin plastic tube which is inserted into a large vein. Common side effects include fevers, skin rash, and weight gain due to oedema which is when the body retains fluids, blood pressure may fluctuate and patients are at a higher risk of infections.²³ 
• Cytotoxic agents (methotrexate, cyclophosphamide, azathioprine): cytotoxic agents are drugs that destroy cells. Cytotoxic agents are usually administered alongside cyclosporine A and in some cases corticosteroids as a first-line therapy. Common side effects may include oral mucositis which are mouth sores, it is most often associated with methotrexate. This treatment pathway has a response rate of 41%.¹⁶

New developments in treatment 

As mentioned above, although cyclosporine A has the highest response rate compared to the other first-line treatments as with any treatment there are limitations. Therefore, the following alternatives have been explored:

• Bortezomib: bortezomib is a proteasome inhibitor, a proteasome is a structure that removes unwanted or damaged proteins. This drug is generally used for multiple myeloma, a type of bone marrow cancer. It has been shown to have beneficial effects on a specific subtype of pure red blood cell anaemia which is linked to monoclonal gammopathy which is a condition in which an individual makes up wanted proteins.^24,25,26 
• Rapamycin: Rapamycin also known as sirolimus is an immunosuppressive drug which is used to treat cancer or for organ transplantation. Studies have shown that in patients that have pure red blood aplasia that does not respond to cyclosporine A, there is a response rate of greater than 70% similar to cyclosporine A. Nonetheless, this treatment takes 6 months to have a peak response whereas, the majority of patients on cyclosporine A respond within 6-8 weeks.²⁷ 

Summary

In summary, pure red cell aplasia presents a challenge in treatment due to its rarity and complexities. While immunosuppressive therapy stands as the first-line treatment, its efficacy varies among patients, with non-respondent cases and limitations in suitability for those with renal impairment. Additionally, immunosuppressive therapy can pose risks of adverse effects and relapse. Consequently, ongoing research seeks alternative therapies and supportive care measures to address pure red cell aplasia's multifaceted nature and optimize patient outcomes.