Immunological
The Rare Responsibility: Immune Intelligence
Dear Impossible Readers,
A healthy immune system is surprisingly intelligent. It must identify threats, respond swiftly, eliminate dangers, and then deactivate. At the same time, it must distinguish healthy body tissues from harmful agents and retain memory to respond faster in future encounters. If any of these functions malfunction, the immune system can overreact, respond excessively or for too long, or fail to defend the body adequately. In rare immunological diseases, the immune system can attack healthy cells, trigger inflammation, damage organs through abnormal repair mechanisms, or fail to provide the protection the body needs. These disorders are highly diverse, which is one reason they are so difficult to diagnose and treat. Some stem from excessive immune activity, while others result from immune deficiency. Some primarily affect one organ, while others can involve the entire body.
The following five diseases show the variety of immune malfunction. Warm autoimmune haemolytic anaemia (wAIHA) involves antibodies destroying red blood cells and affects about 17 cases per 100,000 people in Denmark (2015). Systemic sclerosis (scleroderma) combines immune dysfunction with vascular injury and fibrosis, causing abnormal collagen in skin and organs. Sjögren’s disease primarily affects tear and saliva glands but can impact joints, lungs, kidneys, and nervous tissue. Immune-mediated necrotising myopathy (IMNM) targets skeletal muscles, leading to weakness and fibre destruction, often with antibodies against HMGCR or SRP. Conversely, idiopathic CD4 lymphocytopenia (ICL) results in low CD4 T-cell levels, increasing infection risk. These conditions show the immune system’s broad range of malfunction.
Existing medicines manage these diseases effectively, but most treatments focus on controlling symptoms of immune dysfunction rather than addressing the root cause. In wAIHA, corticosteroids are a mainstay, with rituximab, splenectomy, and other immunosuppressants used if the disease persists or recurs. For systemic sclerosis, treatment varies by affected organs and aims to relieve symptoms, prevent complications, and slow disease progression. However, there is currently no cure. Sjögren’s disease management is similar, depending on organ involvement, utilising artificial tears and saliva substitutes for dryness, and employing drugs like corticosteroids, antimalarials, or immunomodulators for systemic symptoms often off-label. IMNM typically requires aggressive immunosuppressive therapy, usually combining corticosteroids with intravenous immunoglobulin or steroid-sparing agents, and some patients need rituximab or multiple therapies simultaneously. ICL presents a unique challenge because no disease-correcting treatment is available. Care mainly focuses on preventing and treating opportunistic infections, with experimental approaches to increase CD4 counts.
Future developments aim to shift from broad immune suppression to targeting specific disease mechanisms. Researchers focus on precise targets like antibodies, cytokine pathways, and B-cell signalling. For example, wAIHA has a growing pipeline of therapies targeting complement and immune response components. Sjögren’s disease shows rapid progress, with phase 3 trials of ianalumab demonstrating positive results in 2025. Efforts also continue to refine treatments for diseases like IMNM, where current therapies rely on immunosuppressants rather than specific solutions. The goal is to move beyond broad immune suppression to identify and target the specific immune malfunction.
For rare immunological diseases, actions depend on whether the immune system attacks the body or fails to protect it. In warm autoimmune haemolytic anaemia, prompt evaluation and treatment to stop red blood cell destruction are crucial to prevent complications. Regular monitoring is vital in systemic sclerosis and Sjögren’s disease, as organ involvement may develop even with mild initial symptoms. Patients with immune-mediated necrotising myopathy need early specialist care and rehab to reduce muscle damage. For idiopathic CD4 lymphocytopenia, preventing and quickly treating opportunistic infections is key, often requiring expert advice on prophylaxis, vaccinations, and infection monitoring. Overall, immune therapy is not one-size-fits-all. Management should be tailored based on disease mechanisms, affected organs, and immunosuppression risks. The best approach includes accurate diagnosis, referral to experienced clinicians in rare immune conditions, regular complication assessments, and exploring clinical trials.
My dear, responsible readers, I know I missed the rare May and July. My apologies for the delay. I hope to catch up with you soon in the next rare post.
Yours Possibly
Which rare disease category would you like me to cover next?
Further Reading
Baer, A.N., Gottenberg, J.E., St Clair, E.W., Sumida, T., Takeuchi, T., Seror, R., Foulks, G., Nys, M., Mukherjee, S., Wong, R. and Ray, N., 2021. Efficacy and safety of abatacept in active primary Sjögren’s syndrome: results of a phase III, randomised, placebo-controlled trial. Annals of the rheumatic diseases, 80(3), pp.339-348.
Bergua, C., Chiavelli, H., Allenbach, Y., Arouche-Delaperche, L., Arnoult, C., Bourdenet, G., Jean, L., Zoubairi, R., Guerout, N., Mahler, M. and Benveniste, O., 2019. In vivo pathogenicity of IgG from patients with anti-SRP or anti-HMGCR autoantibodies in immune-mediated necrotising myopathy. Annals of the rheumatic diseases, 78(1), pp.131-139.
Bowman, S.J., Fox, R., Dörner, T., Mariette, X., Papas, A., Grader-Beck, T., Fisher, B.A., Barcelos, F., De Vita, S., Schulze-Koops, H. and Moots, R.J., 2022. Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren’s syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial. The Lancet, 399(10320), pp.161-171.
Demir, D.D., Asnaashari, K., Rezaei, N. and Özen, A., 2022. Management of inborn errors of immunity in the genomic era. Turkish Archives of Pediatrics, 57(2), p.132.
Kuter, D.J., Rogers, K.A., Boxer, M.A., Choi, M., Agajanian, R., Arnold, D.M., Broome, C.M., Field, J.J., Murakhovskaya, I., Numerof, R. and Tong, S., 2022. Fostamatinib for the treatment of warm antibody autoimmune hemolytic anemia: Phase 2, multicenter, open‐label study. American Journal of Hematology, 97(6), pp.691-699.
Van Laar, J.M., Farge, D., Sont, J.K., Naraghi, K., Marjanovic, Z., Larghero, J., Schuerwegh, A.J., Marijt, E.W., Vonk, M.C., Schattenberg, A.V. and Matucci-Cerinic, M., 2014. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. Jama, 311(24), pp.2490-2498.
Mammen, A.L., Amato, A.A., Dimachkie, M.M., Chinoy, H., Hussain, Y., Lilleker, J.B., Pinal-Fernandez, I., Allenbach, Y., Boroojerdi, B., Vanderkelen, M. and Delicha, E.M., 2023. Zilucoplan in immune-mediated necrotising myopathy: a phase 2, randomised, double-blind, placebo-controlled, multicentre trial. The Lancet Rheumatology, 5(2), pp.e67-e76.
Michel, M., Terriou, L., Roudot‐Thoraval, F., Hamidou, M., Ebbo, M., Le Guenno, G., Galicier, L., Audia, S., Royer, B., Morin, A.S. and Marie Michot, J., 2017. A randomized and double‐blind controlled trial evaluating the safety and efficacy of rituximab for warm auto‐immune hemolytic anemia in adults (the RAIHA study). American Journal of Hematology, 92(1), pp.23-27.
Régent, A., Autran, B., Carcelain, G., Cheynier, R., Terrier, B., Charmeteau-De Muylder, B., Krivitzky, A., Oksenhendler, E., Costedoat-Chalumeau, N., Hubert, P. and Lortholary, O., 2014. Idiopathic CD4 lymphocytopenia: clinical and immunologic characteristics and follow-up of 40 patients. Medicine, 93(2), pp.61-72.
Sullivan, K.M., Goldmuntz, E.A., Keyes-Elstein, L., McSweeney, P.A., Pinckney, A., Welch, B., Mayes, M.D., Nash, R.A., Crofford, L.J., Eggleston, B. and Castina, S., 2018. Myeloablative autologous stem-cell transplantation for severe scleroderma. New England Journal of Medicine, 378(1), pp.35-47.
Williams, O., 2024. Hematopoietic cell transplantation for inborn errors of immunity: an update on approaches, outcomes and innovations. Current Opinion in Pediatrics, 36(6), pp.653-658.
Zonios, D.I., Falloon, J., Bennett, J.E., Shaw, P.A., Chaitt, D., Baseler, M.W., Adelsberger, J.W., Metcalf, J.A., Polis, M.A., Kovacs, S.J. and Kovacs, J.A., 2008. Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors. Blood, The Journal of the American Society of Hematology, 112(2), pp.287-294.