Riedel’s Thyroiditis: History
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Riedel’s thyroiditis (RT), being strongly connected with positive antibodies against the thyroid, has been traditionally regarded as a particular type of autoimmune thyroiditis. RT was assimilated into the larger spectrum of immunoglobulin IgG4-related disease (IgG4-RD) and, recently (in 2021), a proposal was released to designate a particular framework, namely, IgG4-related thyroid disease (IgG4-RTD) with four underlying entities: IgG4-mediated RT, IgG4-associated Hashimoto’s thyroiditis (and its fibrotic variant), and IgG4-related Graves’s disease.

  • Riedel’s thyroiditis
  • IgG4-related disease
  • thyroidectomy
  • thyroid

1. Riedel’s Thyroiditis: Classical Approach

The classical concept of RT involves a chronic inflammatory condition with a predominantly fibrotic pattern of infiltration located at the thyroid and surrounding areas (parathyroid glands, muscles, trachea, esophagus, local nerves, and vessels). The level of statistical evidence is low (mostly of case reports and series); an estimated incidence of 1 to 1.06 cases per 100,000 people has been estimated, with women being more often affected (female to male ratio of 3–5 to 1), particularly those aged between 30 and 50 years [1][2][3].
Riedel’s thyroiditis results in a thyroid gland that is mostly firm (“woody”, “stony”, or “iron-hard”) and enlarged causing local pain, compressive symptoms (dyspnea, dysphagia, hoarse voice, respiratory insufficiency), and hypothyroidism (up to 80% of cases) in association with extra-thyroid fibrosis; unusual complications such as exophthalmos, Horner’s syndrome, or venous sinus thrombosis have been found as well [1][2][4].
Positive serum antibodies such as anti-thyroid peroxidase and anti-thyroglobulin are identified in 9 out of 10 patients. Blood inflammatory markers such as elevated C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) may be present in typical presentations associated with full-blown clinical manifestations [1][2][5].
Ultrasound and computed tomography might help the imaging diagnosis, particularly to prove the hypoechoic ultrasound pattern in association with avascular gland enlargement at Doppler examination and to show thyroid and extra-thyroid fibrosis extension at computed tomography or magnetic resonance imaging. Furthermore, ultrasound and computed tomography are also used to differentiate RT from malignancy (which is not always feasible unless histological evidence is provided) and to reveal non-thyroid spreading of IgG4-RD. Ultrasound elastography might highlight an elevated stiffness. 18-Fluoro-deoxyglucose positronic emission tomography/computed tomography may point out an increased tracer uptake at first presentation, while technetium (Tc) thyroid uptake is reduced at 99mTc thyroid scintigraphy [1][6][7].
RT confirmation comes from histological reports (in addition to immunohistochemistry analysis) based on lymphocyte infiltration, fibrosis, and destruction of thyroid follicles (which explains the long-standing primary hypothyroidism). No malignant or giant cell should be identified. A high amount of IgG4-carrying plasma cells represents the novel clue of RT. Of course, in order to provide the histological and immunohistochemistry features, an open/core needle biopsy is necessary (unless a thyroidectomy was already performed); thus, an index of suspicion should be kept in mind even in the early stages of the disease when classical clinical signs are not yet very suggestive [1][4][8].
Misdiagnosis as Hashimoto’s thyroiditis (mostly due to positive serum antibodies against the thyroid) or as a thyroid malignancy, particularly of anaplastic carcinoma, sarcoma, or primary thyroid lymphoma, is often described considering the anatomical aspects and progressive (severe) clinical evolution [1][9]. Delay of the diagnosis underlines a time window from presentation to histological confirmation varying between a few months and 2 years (a median of 4 months) [1][4].
Prompt intervention might improve the outcome. There is no consensus therapy in RT, which is rather a matter of individual decision, but glucocorticoid treatment (for instance, with prednisone, prednisolone, or dexamethasone) represents the first choice of medication. Currently, rituximab, a monoclonal antibody against CD20 protein, may be regarded as a second-line therapy. Tamoxifen (10–20 mg twice per day) has a longer history of use than rituximab as an additional drug to corticoids; it may be added to them or even offered as a single medication. This selective estrogen receptor modulator is beneficial not through its anti-estrogen capacity but via anti-fibrotic effects by stimulating transforming growth factor (TGF-β), a cytokine released by fibroblasts and epithelial cells acting as a growth inhibitor of various cells (including fibroblasts) [10][11]. The need for anti-fibrotic effects also indicates mycophenolate mofetil (1 g twice per day) which is approved for systemic fibrosis, but it has limited applications due to severe side effects (pancytopenia or renal function damage) [1][4][12].
Low-dose radiation therapy at the thyroid level represents a rarely applied alternative [13]. Surgery, despite not being a first choice of therapy, is useful for surgical biopsy (since fine needle aspiration is not helpful in more than 75% of cases), for refractory cases to medical therapy, or for emergency tracheostomy [1][2][4]. Generally, the presence of fibrosis and invasion of surrounding areas increases the rate of post-thyroidectomy complications or failure to completely remove the thyroid gland [14][15][16]. However, in cases of RT, it helps to prove a pathological confirmation. On the contrary, a patient who is mistakenly diagnosed with RT and actually has an alternative diagnosis may benefit from a post-operatory histological report [17][18].
The natural history of RT is progression but spontaneous regression or episodes of relapse are reported in addition to medically-induced remission, which is mostly due to glucocorticoids. Disease-related mortality is rather low, but a severe impairment of quality of life is reported due to multiple complications and long-term medication [1][4].
Novel practical approaches to RT connect the disease with the larger area of IgG4-RD in terms of serum IgG4 assays but, mostly, the intra-thyroid IgG4 findings reflect their essential role in RT. The importance of serum IgG4 assays has been suggested for daily practice purposes and further guidelines are required. Controversies related to their low predictive value and correlations with active or inactive stages of the condition are still ongoing. Immunohistochemistry-based IgG4 stain is mandatory for RT confirmation by pointing out a high amount of IgG4-carrying plasma cells, and an increased IgG4/IgG ratio [19].

2. Immunoglobulin G4-Related Disease

IgG4-RD, a rare immunologic condition, presents as single or multi-organ/tissue spreading at pulmonary, orbital areas, salivary glands (such as chronic sclerosing sialadenitis, also named Kűttner tumor, and Mikulicz’s disease), biliary ducts and in the gallbladder (sclerosing cholangitis and cholecystitis), renal system (interstitial nephritis), pancreatic system (multifocal autoimmune pancreatitis), and lymph nodes in association with various cardiovascular manifestations (such as aortitis, pericarditis, vasculitis, and pulmonary vascular disease) [20][21][22][23][24]. Virtually, any organ may become a host of the condition [25]. This non-malignant, fibro-inflammatory disease requires a multidisciplinary team since it involves a heterogeneous presentation, thus awareness is essential despite a rather low epidemiologic impact (it is currently being considered an orphan disease) [26][27].
An IgG4-associated entity was first reported more than two decades ago (in 2001) in terms of pancreatitis (and further conceptual data were soon published in 2003) [28][29]; however, overall IgG4 dynamics massively changed over the years, with RT being recognized as part of this spectrum only one decade later and included in the IgG4-RD guideline from 2019 [30][31][32].
At the onset, the lesions might mimic a malignancy (or a paraneoplastic syndrome) or an infectious disease or they may be mistaken as another autoimmune condition, while severe cardiac and vessel involvement should be differentiated from an acute myocardial infarction or rupture of an aortic aneurysm [23][27][33]. Functional imaging with 18-Fluoro-deoxyglucose positronic emission tomography/computed tomography, despite not being specific, represents a useful tool to indicate the sites of IgG4-mediated increased activity in addition to traditional ultrasound, computed tomography, and magnetic resonance imaging-based findings [34][35].
The pathogenic traits of RT are yet poorly understood and are mostly related to polyclonal activation of plasma cells [26]. The serologic hallmark is represented by the elevated IgG4 subtype [20]. Genetic susceptibility regarding CFHR1 and CFHR4 gene deletions has been suggested [23][36]. The highly specific histologic features include an increased (dense) lymphoplasmacytic infiltration, high content of IgG4-positive plasma cells, storiform fibrosis, and (obliterate) phlebitis [20][22]. Needle biopsy is less likely to point out all these mentioned traits compared with surgical (open) biopsy depending on the organ and disease severity [37].
In terms of treatment, firstly, patients are candidates for glucocorticoid therapy, which might rapidly improve the clinical evolution in the majority of cases; thus, prompt and adequate disease recognition and intervention is important (if feasible) [22]. Non-responders are offered second-line medication such as rituximab, as well as other drugs such as cyclophosphamide or mycophenolate mofetil, etc. [20][26][38]. Surgical interventions are required in selected cases, typically after the failure of medical management. Sometimes, interventions include emergency procedures as seen in vascular complications (for instance, valve replacements) [39][40][41].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11061691

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