Tumor necrosis factor (TNF)-α plays a central role in the pathogenesis of chronic inflammatory diseases, such as rheumatoid arthritis (RA). The introduction of TNF-α inhibitors has markedly improved disease control and reduced joint destruction in patients with refractory RA. However, paradoxical immune phenomena—autoimmune or inflammatory reactions that emerge despite cytokine blockade—have been increasingly reported, including psoriasis, lupus-like syndromes, vasculitis, and thyroiditis (1–4). These reactions are thought to result from complex cytokine network alterations following TNF-α inhibition (5).

Destructive thyroiditis is a self-limited inflammatory disorder characterized by follicular cell destruction and transient thyrotoxicosis. While viral infections and autoimmune mechanisms are common causes (6–8), biologic agents have also been implicated in rare cases (1, 2, 9–13). Several reports have documented thyroid dysfunction or granulomatous thyroiditis during anti-TNF therapy, suggesting that TNF-α blockade may disturb immune tolerance within the thyroid gland.

Serum amyloid A (AA) amyloidosis is another serious systemic complication of long-standing inflammatory diseases, including RA. Persistent elevation of serum AA (SAA) leads to extracellular amyloid deposition in multiple organs, most commonly the kidneys and gastrointestinal tract (3, 14–19). Although biologic therapy can reduce the risk of amyloid progression by suppressing inflammation, paradoxically, abrupt immune modulation may also alter cytokine balance and unmask subclinical amyloid deposition (18, 20–22).

To the best of our knowledge, no previous report has described the sequential occurrence of destructive thyroiditis and clinically overt AA amyloidosis following anti-TNF-α therapy. Here, we report a patient with long-standing RA who developed destructive thyroiditis and acute renal failure after treatment with certolizumab pegol (CZP). This case provides novel insight into how TNF-α inhibition can induce an immune shift that triggers both autoimmune thyroid injury and the manifestation of latent AA amyloidosis.

A 71-year-old man with a 16-year history of seropositive RA was referred to our department for worsening joint pain and swelling despite treatment with methotrexate (6 mg/week), salazosulfapyridine (1,000 mg/day), and low-dose prednisolone. The patient had no known family history of amyloidosis or hereditary autoinflammatory diseases. Laboratory evaluation showed elevated C-reactive protein (CRP, 7.6 mg/dL), erythrocyte sedimentation rate (58 mm/h), and matrix metalloproteinase-3 (1,650 ng/mL). Rheumatoid factor and anti-cyclic citrullinated peptide antibody levels were markedly increased (393 IU/mL and >500 U/mL, respectively). Laboratory findings before and after biologic therapy are summarized in Table 1.

Clinical findings before and after anti–TNF-α antibody therapy are summarized in Figure 1. Owing to inadequate disease control despite conventional synthetic DMARD therapy, certolizumab pegol (CZP), an anti–TNF-α biologic agent, was initiated. CZP was administered as a loading regimen of 400 mg subcutaneously at baseline, at week 2, and at week 4, followed by a maintenance dose of 200 mg subcutaneously at week 6.

After the fourth injection of CZP, the patient developed anterior neck pain, swelling, and low-grade fever. Computed tomography performed on day 12 of admission revealed diffuse enlargement of the thyroid gland with low attenuation areas (Figure 2). Laboratory testing indicated thyrotoxicosis (free thyroxine = 4.31 ng/dL, thyroid-stimulating hormone = 0.04 μU/mL) with markedly elevated thyroglobulin levels (1,000 ng/mL). Purulent thyroiditis was initially suspected, and cefditoren pivoxil was administered. The neck pain improved within two weeks, and thyroid function gradually normalized after discontinuation of CZP. However, systemic inflammation persisted, and two weeks later the patient developed nausea, diarrhea, and acute renal dysfunction (estimated glomerular filtration rate [eGFR] = 11.8 mL/min/1.73 m²).

Despite hydration and corticosteroid therapy, renal impairment and diarrhea worsened. Serum amyloid A (SAA) was markedly elevated (461.9 μg/mL; reference <8 μg/mL). Gastrointestinal endoscopy and renal biopsy demonstrated amyloid deposition with positive Congo red staining in both the duodenal and renal interstitium, establishing the diagnosis of AA amyloidosis (Figure 3). The temporal clinical course is summarized in Figure 4. The clinical course suggested that latent amyloidosis became clinically apparent following immune modulation induced by TNF-α blockade.

Given the diagnosis of RA-associated AA amyloidosis, certolizumab was permanently discontinued and treatment with tocilizumab (TCZ, 162 mg every two weeks) was initiated. CRP levels normalized within one month, and diarrhea and renal function improved rapidly, with eGFR stabilizing at approximately 30 mL/min/1.73 m². After one year of TCZ therapy, the patient remained asymptomatic with normal thyroid function and without proteinuria.

Although elevated serum thyroglobulin levels and a self-limited clinical course can be observed in both classic subacute thyroiditis and destructive thyroiditis, we favored destructive thyroiditis in the present case based on the overall pattern of transient thyrotoxicosis due to follicular injury rather than sustained thyroid hormone overproduction. As described in prior reviews, destructive thyroiditis is characterized by the release of preformed thyroid hormone, a transient thyrotoxic phase, and spontaneous resolution without the need for antithyroid therapy, in contrast to Graves’ disease, which is driven by ongoing hormone synthesis (23, 24).

In the present case, Graves’ disease was considered unlikely because thyroid-stimulating hormone receptor antibody (TRAb) was low (4.4%), thyroid peroxidase antibody (TPO Ab) was minimally elevated (7 IU/mL), and thyrotoxicosis resolved spontaneously after discontinuation of CZP without antithyroid therapy.

Although thyroglobulin antibody (TgAb) was modestly elevated (49 IU/mL), this finding alone was insufficient to support autoimmune hyperthyroidism, as discussed in prior reviews of thyroiditis (23, 24).

Classic subacute thyroiditis was also considered; however, the temporal association with TNF-α blockade and the clinical course following drug discontinuation suggested an immune modulation–associated destructive process. Suppurative thyroiditis was initially suspected; however, the absence of abscess formation on imaging and clinical improvement without surgical drainage argued against a bacterial etiology. Although thyroid ultrasonography and radioactive iodine uptake (RAIU) testing ware not performed, the available clinical, laboratory, and imaging findings, together with established diagnostic frameworks for thyroiditis, collectively supported the diagnosis of destructive thyroiditis (23, 24).

Systemic AA amyloidosis is a serious complication of chronic inflammatory diseases, such as RA, resulting from persistent elevation of SAA and subsequent tissue deposition (3, 14–19). Biologic agents targeting TNF-α have dramatically improved the management of RA, but paradoxical autoimmune and inflammatory reactions have also been increasingly recognized (1–4). The present case illustrates a rare phenomenon in which anti-TNF-α therapy appeared to unmask latent AA amyloidosis while simultaneously inducing destructive thyroiditis.

The patient reported significant distress during the period of thyroiditis and renal dysfunction due to worsening physical symptoms and uncertainty regarding the diagnosis.

Following the initiation of tocilizumab therapy, he experienced marked improvement in daily activities and expressed satisfaction with the treatment outcome.

This case illustrates a rare but important paradoxical immune reaction associated with TNF-α inhibition in RA. The sequential development of destructive thyroiditis and overt AA amyloidosis following CZP therapy suggests that TNF-α blockade can profoundly alter cytokine homeostasis, potentially unmasking latent inflammatory complications. Our findings highlight the delicate balance between therapeutic immune suppression and unintended immune activation during biologic therapy. Monitoring thyroid function, renal parameters, and SAA levels before and during anti-TNF treatment may facilitate early recognition of such adverse events. Moreover, the rapid improvement observed after switching to an IL-6 receptor inhibitor underscores the pivotal role of IL-6 in both amyloidogenesis and paradoxical inflammation. Clinicians should remain vigilant for unexpected autoimmune or inflammatory manifestations during biologic therapy and tailor cytokine-targeted treatments according to the evolving immunological profile of each patient.