Barts-MS rose-tinted-odometer: ★★★ (mid-summer orangey-yellow #f5bd1f)
As you are aware if you choose to be treated with the most effective IRTs (immune reconstitution therapies) you stand a relatively high chance of developing a second autoantibody-mediated autoimmune disease, with thyroid disease being the most common. For example, the cumulative incidence of second autoimmune diseases post-alemtuzumab is ~45%. In other words, if you want a potential cure from MS with these treatments you need to be prepared to get a second autoimmune disease.
At present secondary autoimmunity seems to be more common post-alemtuzumab when compared to AHSCT and we haven’t seen this complication with cladribine, but I suspect there will be isolated cases. The true incidence of these autoantibody-mediated problems post-AHSCT is not known, but is clearly an issue and I am beginning to wonder why we don’t put in place the same monthly blood and urine monitoring post-AHSCT as we do post-alemtuzumab.
By far the commonest is autoimmune thyroid disease with about 20% of males and 40% of females with MS being treated with alemtuzumab developing autoimmune thyroid disease. The type of autoimmune thyroid disease post-IRT is not quite the same as standard Grave’s disease. It tends to be more brittle with frequent fluctuations and even remissions. The reason for this is that post-IRT Grave’s disease tends to have stimulatory antibodies against the thyrotropin receptor, which activates the thyroid gland to produce thyroid hormone. These anti- thyrotropin receptor antibodies don’t seem to damage the thyroid gland in the same way as other anti-thyroid gland antibodies. Despite this many patients end up with hypothyroidism and need to go onto thyroxine or thyroid replacement therapy.
NOTE: “ Levothyroxine is best taken on an empty stomach 30 minutes before food, and not to be taken with caffeine. This is not commonly taught and may be a cause for poor response—so worth sharing”. Simon Hodes. Investigating hypothyroidism: how to take levothyroxine.BMJ 2021;373:n1463
The following figure and review paper is worth reading if you are more interested in the diagnosis and management of thyroid problems post IRTs.
a) Hyperthyroidism/thyrotoxicosis. b) Hypothyroidism. TSH, thyroid-stimulating hormone; TRAb, thyrotropin receptor autoantibodies; FT4, free-thyroxine; FT3, free-triiodothyronine; GD, Graves’ disease; ATD, antithyroid drug; RAI, radioiodine; TPOAb, autoantibodies to thyroid peroxidase; LT4, levothyroxine. Image from Eur Thyroid J.
Muller et al. 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy. Eur Thyroid J. 2019 Jul;8(4):173-185.
Thyroid dysfunction (TD) frequently occurs as an autoimmune complication of immune reconstitution therapy (IRT), especially in individuals with multiple sclerosis treated with alemtuzumab, a pan-lymphocyte depleting drug with subsequent recovery of immune cell numbers. Less frequently, TD is triggered by highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV), or patients undergoing bone-marrow/hematopoietic-stem-cell transplantation (BMT/HSCT). In both alemtuzumab-induced TD and HIV/HAART patients, the commonest disorder is Graves’ disease (GD), followed by hypothyroidism and thyroiditis; Graves’ orbitopathy is observed in some GD patients. On the contrary, GD is rare post-BMT/HSCT, where hypothyroidism predominates probably as a consequence of the associated radiation damage. In alemtuzumab-induced TD, the autoantibodies against the thyrotropin receptor (TRAb) play a major role, and 2 main aspects distinguish this condition from the spontaneous form: (1) up to 20% of GD cases exhibit a fluctuating course, with alternating phases of hyper- and hypothyroidism, due to the coexistence of TRAb with stimulating and blocking function; (2) TRAb are also positive in about 70% of hypothyroid patients, with blocking TRAb responsible for nearly half of the cases. The present guidelines will provide up-to-date recommendations and suggestions dedicated to all phases of IRT-induced TD: (1) screening before IRT (recommendations 1-3); (2) monitoring during/after IRT (recommendations 4-7); (3) management of TD post-IRT (recommendations 8-17). The clinical management of IRT-induced TD, and in particular GD, can be challenging. In these guidelines, we propose a summary algorithm which has particular utility for nonspecialist physicians and which is tailored toward management of alemtuzumab-induced TD. However, we recommend prompt referral to specialist endocrinology services following diagnosis of any IRT-induced TD diagnosis, and in particular for pregnant women and those considering pregnancy.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.