Dental amalgam associated with SAPHO syndrome and IgA nephropathy: a case report and literature review

Abstract

Background

Exposure to metals is associated with adverse health effects, including multiorgan damage and dysregulation of systemic immune responses. The increasing use of metallic implants in humans, such as dental materials and orthopedic devices, has resulted in chronic endogenous exposure to metal ions. The pathophysiological mechanisms underlying implant-related complications and their clinical implications have not been fully elucidated.

Case presentation

We present a case of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome coexisting with IgA nephropathy (IgAN) in the context of dental amalgam exposure. Following amalgam placement, the patient developed palmoplantar pustulosis (PPP) and sternoclavicular arthritis, with a subsequent diagnosis of IgAN. Notably, all the clinical manifestations were markedly resolved after amalgam removal.

Conclusion

This case suggests a potential link between SAPHO syndrome, IgAN, and dental amalgam exposure. To our knowledge, this is the first reported case linking these conditions. Further studies are needed to elucidate the mechanisms and clinical implications of metal-induced autoimmune or inflammatory responses.

Clinical trial number

Not applicable.

Introduction

Exposure to metals has been linked to various adverse health effects, including damage to the skin, kidneys, respiratory system, and digestive system, as well as systemic immune dysregulation [1]. Humans are exposed to metals through multiple routes, including environmental pollution, occupational exposure, contaminated food consumption, and contact with metal-containing products (e.g., cosmetics). In recent years, the use of metallic implants, including dental materials, orthopedic devices, endovascular stents, and cardiac pacemakers, has seen a significant increase [2]. All metallic implants undergo corrosion, resulting in chronic endogenous exposure to metal ions [3]. The pathophysiological mechanisms underlying implant-related complications and their clinical consequences remain incompletely understood. We report a case of dental amalgam associated with synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome and IgA nephropathy (IgAN). To our knowledge, this is the first report linking SAPHO syndrome and IgAN to dental amalgam exposure.

Case report

A 50-year-old man with a 4-month history of proteinuria was admitted to our hospital on December 25, 2018. He had a 7-year history of hypertension, a 2-year history of type 2 diabetes mellitus and palmoplantar pustulosis (PPP), and a 7-month history of right sternoclavicular joint arthritis. The patient was on oral medications, including metformin for diabetes management, metoprolol and furosemide for hypertension, and ibuprofen for sternoclavicular arthritis. He used corticosteroid creams and unspecified traditional Chinese herbal formulations intermittently for PPP. The patient had amalgam fillings placed 4 years prior for dental caries. He had no history of tonsillitis or periodontitis and reported no known allergies. He had a 10-year history of smoking but had quit 2 years prior, at the same time he ceased alcohol consumption. Upon admission, the patient had a blood pressure of 130/88 mm Hg and a body mass index (BMI) of 25.8 kg/m². Dermatologic examination revealed erythematous swelling with localized tenderness over the right sternoclavicular joint (Fig. 2a) and scattered erythematous plaques accompanied by millet-sized papules and desquamation on the palms and soles (Fig. 1b). No pharyngeal congestion or tonsillar enlargement was observed. The patient’s lungs were clear bilaterally, his heart rate was 75 beats/min with a regular rhythm, and there was no lower limb edema.

Fig. 1

Changes in PPP lesions on the palms. (a) Initial skin presentation at diagnosis: extensive scaly erythema and multiple pustulovesicular lesions. (b) Skin presentation at admission: scattered erythematous plaques accompanied by millet-sized papules and desquamation. (c) Skin presentation 5 years post discharge: no skin lesions

Laboratory findings upon admission are summarized in Table 1. Blood analysis revealed a white blood cell count of 7.94 × 10⁹/L, neutrophil percentage of 54.60%, eosinophil percentage of 5.80%, red blood cell count of 4.88 × 10¹²/L, hemoglobin level of 157.00 g/L, and platelet count of 302.00 × 10⁹/L. C-reactive protein level was 6.66 mg/L. Urinalysis showed occult blood (2+), protein (2+), and a red blood cell count of 80.9/µL. The urine protein quantification was 864.96 mg/day. Urine protein electrophoresis results are detailed in Table 1. Serum chemistry analysis revealed glucose level of 7.64 mmol/L, creatinine level of 81.18 µmol/L, blood urea nitrogen level of 5.47 mmol/L, uric acid level of 355.77 µmol/L, and albumin level of 38.03 g/L. The erythrocyte sedimentation rate was 23.00 mm/h. Immunoglobulin levels and complement system levels are also summarized in Table 1. The HbA1c level was 7.60%. Thyroid function tests, rheumatoid factor levels, ANA spectra, ANCAs, and tumor marker levels were within normal limits. Serology for HIV, hepatitis B, and hepatitis C was negative. Throat swab culture was negative. Renal ultrasound revealed a normal kidney size and morphology. CT imaging revealed marginal hyperostosis, an ill-defined articular cortex in the right sternoclavicular joint and osteolytic changes in the right first sternocostal joint (Fig. 2b). A whole-body bone scan using 99mTc-MDP demonstrated increased radiotracer uptake at the right sternoclavicular joint and the costal cartilage of the first rib, indicative of active bone metabolism (Fig. 3).

Table 1 Laboratory data upon admission

Fig. 2

Clinical manifestations of sternoclavicular arthritis. (a) Erythematous swelling over the right sternoclavicular joint. (b) CT imaging revealed an ill-defined articular cortex in the right sternoclavicular joint (white arrow) and osteolytic changes in the right first sternocostal joint (yellow arrow)

Fig. 3

Whole-body bone scan images revealing active bone metabolism in the right sternoclavicular joint and the costal cartilage of the first rib

A renal biopsy performed on January 3, 2019, revealed 20 glomeruli under light microscopy, among which 3 exhibited global sclerosis. The remaining glomeruli exhibited mild to moderate mesangial cell hyperplasia and matrix expansion, with fuchsinophilic protein deposition in the mesangial region. No endocapillary hypercellularity or mesangial interposition was observed. A single small cellular crescent was noted. Tubules showed vacuolation and granular degeneration, with patchy atrophy and scattered inflammatory cell infiltration in the interstitium. Immunofluorescence of frozen sections revealed diffuse, granular IgA (3+) and C3 (+) deposits in the mesangium, while IgG, IgM, and C1q were negative. Paraffin-embedded sections were subjected to double-immunofluorescence staining. The results showed KM-55 (an antibody to galactose-deficient IgA1 [Gd-IgA1]) (2+), primarily in the mesangial areas, overlapping with IgA (2+). Electron microscopy (EM) revealed electron-dense deposits predominantly located in the mesangial areas, with no subepithelial humps observed. There was partial foot process fusion and no significant glomerular basement membrane thickening. The pathological diagnosis was IgAN with the Oxford classification: M1E0S0T0C1 (Fig. 4).

Fig. 4

Renal biopsy findings. (a-b) Immunofluorescence: (a) IgA (3+) mesangial deposition (×400); (b) C3 (+) mesangial deposition (×400). (c) Light microscopy: small cellular crescent (Jones silver stain ×400). (d-f) Double-immunofluorescence staining for IgA and KM-55: (d) IgA (2+) mesangial deposition (×400); (e) KM-55 (2+) mesangial deposition (×400); (f) merged image: KM-55 was colocalized with IgA (×400). (g-i) EM: electron-dense deposits mainly in mesangial areas, no subepithelial humps (g-h×6000, i×8000)

The patient had PPP for 2 years prior to admission. The initial skin lesions included extensive scaly erythema and multiple pustulovesicular lesions on the palms and soles (Fig. 1a). Even with smoking cessation (known to alleviate PPP symptoms [4]) and the use of corticosteroid creams combined with Chinese herbal formulations, the symptoms remain unresolved. Subsequently, sternoclavicular arthritis developed, which was unresponsive to ibuprofen (intermittent use for 1 month). Proteinuria was detected 2 months after discontinuation of ibuprofen. The dental amalgam fillings were removed 2 months before admission due to persistent PPP symptoms, as recommended by the dentist. Significant improvement in the skin lesions was observed at the time of admission (Fig. 1b). During hospitalization, the patient was advised to follow a low-sodium diet and was treated with oral valsartan 160 mg daily for IgAN. After discharge, the patient self-discontinued the dietary regimen and switched from valsartan to nifedipine. Valsartan had been used for no more than 1 week. Additionally, all topical/oral medications for PPP and sternoclavicular arthritis were discontinued. Five months later, tenderness, swelling, and erythema of the right anterior chest wall had resolved, and palmar/plantar rashes, papules, and desquamation had gradually faded. Urinalysis revealed occult blood (±) and protein (±), with urine protein quantification decreasing to 121.77 mg/day. Owing to the Coronavirus disease 2019 (COVID-19) pandemic, the patient missed scheduled follow-up visits. On January 8, 2024, the patient returned for re-evaluation. Over the past 5 years, there has been no recurrence of sternoclavicular arthritis or PPP (Fig. 1c). Follow-up urinalysis showed protein (±) and occult blood (−), with a urine protein quantification of 146.0 mg/day and serum creatinine of 94.0 µmol/L. The changes in urinary protein quantification before and after the removal of amalgam are shown in Fig. 5.

Fig. 5

Changes in urinary protein quantification before and after the removal of amalgam

Discussion

We present the first reported case of SAPHO syndrome complicated by IgAN, potentially associated with dental amalgam exposure. The diagnosis of SAPHO syndrome was established on the basis of PPP, sternoclavicular arthritis, and characteristic imaging findings on CT and 99mTc-MDP whole-body bone scan, following rigorous exclusion of infectious, autoimmune, malignant, and other etiologies. SAPHO syndrome, a rare disorder, remains a diagnostically challenging entity due to its heterogeneous presentation, the absence of universally validated diagnostic criteria, and the potential temporal separation of clinical features, which can span several years, as demonstrated in this case [5,6,7,8]. Skin lesions, particularly PPP, accounting for 50-75% of all dermatological manifestations, serve as key diagnostic clues for SAPHO syndrome [7]. The predominant osteoarticular features include hyperostosis and osteitis, with a predilection for the anterior chest wall, especially the sternoclavicular and first sternocostal joints in adults [9]. Current therapeutic strategies for SAPHO syndrome primarily involve nonsteroidal anti-inflammatory drugs (NSAIDs) as first-line treatment, followed by bisphosphonates, biologic agents, particularly tumor necrosis factor-α (TNF-α) inhibitors, and glucocorticoids, among others [10]. This patient’s symptoms failed to respond to conventional interventions. Notably, progressive improvement in SAPHO syndrome was observed following amalgam removal, the temporal correlation strongly suggests a potential pathogenic link among SAPHO syndrome and amalgam exposure.

Amalgam, an alloy containing mercury, silver, tin, zinc, and copper is less commonly used as a dental filling material today [11]. According to the Minamata Conventions Full National Reports 2021, 43 countries have banned the use of dental amalgam by law. China has announced that amalgam is prohibited for deciduous teeth, patients under 15, and pregnant/breastfeeding women. Exposure to mercury and other metal ions from such alloys occurs primarily through two mechanisms: ingestion of salivary corrosion products and direct absorption into the bloodstream [12]. To date, several studies have established a correlation between exposure to metal alloys and the etiology of skin diseases, especially PPP, as well as skeletal and joint disorders [13]. A systematic review (1964–2018) found that 22.7% of PPP patients had documented allergies, with 84.3% involving metal hypersensitivity (e.g., tin, copper, mercury, nickel). Notably, 65.1% of these patients achieved clinical improvement after metal avoidance [14]. Roed-Petersen et al. [15] reported osteomyelitis associated with nickel allergy, Hayashi et al. [16] described sternal osteomyelitis and contact dermatitis due to nickel/cobalt hypersensitivity to stainless steel wires, and Wen et al. [17] reported PPP and osteomyelitis linked to a copper-containing intrauterine device; in all cases, symptoms were alleviated following the removal of the metal implants. SAPHO syndrome is now increasingly considered an autoinflammatory disorder [18]. Cytokines, including TNF-α, interleukin-1β (IL-1β), interleukin-6 (IL-6), among others are central mediators of SAPHO syndrome pathogenesis. Metals can act as potent immunomodulators, disrupting immune homeostasis and leading to Th1/Th2 imbalance and cytokine network dysregulation. They can also inappropriately activate lymphoid subsets involved in antigen-specific immunity, alter the immune response repertoire, and modify antigen presentation, potentially resulting in chronic inflammation and autoimmune disorders [19]. Given these mechanisms, it is plausible that amalgam exposure may contribute to the development of SAPHO syndrome by triggering the underlying inflammatory processes.

In this case, given the patient’s history of type 2 diabetes, vigilance is required for the potential risk of IgA-dominant infection-related glomerulonephritis (IgA-IRGN). However, no signs of infection were observed. Serum complement levels were normal, and EM showed no subepithelial humps, which are commonly seen in IgA-IRGN [20]. Emerging evidence indicates that KM-55 positivity is not exclusive to primary IgAN and may also occur in IgA-IRGN, but the intensity of the deposits in the latter is significantly lower than in primary IgAN [21]. A study identified an optimal cutoff value of 0.5 + for differentiating between these two entities [20]. In this case, KM-55 was positive at 2 + intensity, matching IgA. Based on these results, we believe IgA-IRGN can be excluded. The patient did not receive immunosuppressive therapy specifically targeting IgAN. Proteinuria developed two months after ibuprofen cessation, with an unlikely association between drug discontinuation and proteinuria reduction. Valsartan had been used for less than 1 week, making it difficult to attribute the reduction in proteinuria to its action. Nifedipine may indirectly reduce proteinuria in IgAN through blood pressure reduction, but its antiproteinuric effect is relatively weak. Guidelines do not recommend it for use as a single agent for proteinuria reduction. The remission of the patient’s IgAN and SAPHO syndrome occurred in parallel, both following the removal of dental amalgam. Neither condition has relapsed in the more than 5 years since then. This intriguing observation suggests that amalgam may be a triggering factor for both conditions. Additionally, it is plausible that addressing the underlying inflammatory state of SAPHO syndrome had a beneficial effect on IgAN, as inflammatory cytokines such as TNF-α also appear to play a key role in the pathophysiology of IgAN [22].

Reports of SAPHO syndrome combined with IgAN are exceedingly rare. Morimoto et al. [23] and Li et al. [24] described cases of SAPHO syndrome complicated by IgAN with nephrotic syndrome and IgA vasculitis nephritis, respectively. Noda et al. [25] and Shimamura et al. [26] reported cases of IgAN coexisting with PPP and sternoclavicular arthritis. In these cases, tonsillar infection or allergen exposure was considered a factor in the onset or exacerbation of both SAPHO syndrome and IgAN, with symptoms alleviated following tonsillectomy or anti-allergic treatment. This phenomenon suggests that there may be overlapping pathogenic mechanisms between SAPHO syndrome and IgAN, which is consistent with our case. The relationship between metal exposure and IgAN remains less explored. Several case reports have linked the exposure of metals, including cadmium, nickel, and mercury, to IgAN. In these cases, IgAN typically presents with microscopic hematuria, proteinuria, or nephrotic syndrome, with most patients exhibiting normal renal function. The latency period between exposure and symptom onset ranges from several months to years, and most patients achieve complete renal recovery after exposure cessation (Table 2). The clinical presentation in our case aligns with these reported characteristics. Interestingly, if exposure to amalgam leads to IgAN, the mechanism by which metals induce the production of Gd-IgA1requires further investigation.

Table 2 Clinical features of metal-related IgAN

Based on our understanding of the disease mechanisms and the clinical progression observed in this case, we speculate that dental amalgam exposure may have precipitated concurrent SAPHO syndrome and IgAN, potentially through shared pathways of metal-induced immune dysregulation. Given the expanding utilization of various metallic implants in clinical practice, we emphasize the critical need for further research into the mechanisms of metal-induced tissue injury and their potential clinical implications.

In summary, this article reports a case of SAPHO syndrome and IgAN potentially triggered by dental amalgam exposure. To date, no similar cases have been reported in the literature. Our study has several limitations: the exact composition of the dental amalgam was not analyzed, patch testing for metal hypersensitivity was not performed, and serum and urinary metal concentrations were not quantified. Despite these limitations, the patient achieved clinical remission following amalgam removal, highlighting the need for clinicians to maintain vigilance regarding potential metal exposures during medical history assessments to avoid misdiagnosis.