Detecting Amyloid Goiter With 99mTc-PYPSPECT/CT in the Setting of Ankylosing Spondylitis An Uncommon Involvement of AA Amyloidosis

First author: Denizmen et al

Review: Clinical nuclear medicine

Reference : DOI : 10.1097/RLU.0000000000005280

Link to article : https://pubmed.ncbi.nlm.nih.gov/38967510/

Case Report:

The authors present the case of a 43-year-old Turkish man who had been followed for ankylosing spondylitis (AS) since the age of 16. He later developed severe AA amyloidosis with end-stage renal failure and underwent a kidney transplant. A 99m Tc-PYP scintigraphy was requested by his cardiologists due to an atypical appearance on a cardiac MRI. This scintigraphy showed minimal cardiac uptake of 99m Tc-PYP but a diffuse accumulation of the tracer in the thyroid gland (figure, panels A, B, and C). PET-CT images revealed increased uptake of 99m Tc-PYP in a diffusely enlarged thyroid gland containing regions with fatty density but no tracer accumulation (figure, panels D and E). There was no gastric contrast uptake, indicating the presence of free technetium (figure, panels F and G). Thyroid ultrasound showed diffuse gland hypertrophy with heterogeneous echogenicity, with hyper-echogenic areas closest to the transducer. A thyroid fine-needle aspiration biopsy revealed homogeneous eosinophilic deposits in the perifollicular region, Congo red-positive staining, and apple-green birefringence under polarized light, confirming amyloidosis (figure, panels J and K). Thyroid function was normal.

AA amyloidosis is a rare complication of spondyloarthropathies, with a reported prevalence between 1.1% and 2.15%. (1)

Amyloid goiter is a late complication of AA amyloidosis, mainly observed after renal amyloidosis, and can result in a rapidly growing goiter, potentially leading to clinical symptoms such as dyspnea, sometimes requiring decompressive surgery.

A study on amyloid goiters in AA amyloidosis secondary to familial Mediterranean fever showed that most patients (75%) were euthyroid, though alterations in thyroid hormone levels could be observed (2).

Conclusion: This is the first case demonstrating 99m Tc-PYP SPECT/CT uptake in an amyloid goiter in a patient with AA amyloidosis secondary to ankylosing spondylitis. This imaging technique could serve as a non-invasive tool to confirm the amyloid nature of a goiter in patients with confirmed AA amyloidosis.

References:

1. Papa R, Lachmann HJ. Secondary, AA, Amyloidosis. Rheumatic Disease Clinics of North America [Internet]. nov 2018 [cité 8 sept 2024];44(4):585‑603. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S0889857X18300577

2. Vergneault H, Terré A, Buob D, Buffet C, Dumont A, Ardois S, et al. Amyloid Goiter in Familial Mediterranean Fever: Description of 42 Cases from a French Cohort and from Literature Review. JCM [Internet]. 5 mai 2021 [cité 8 sept 2024];10(9):1983. Disponible sur: https://www.mdpi.com/2077-0383/10/9/1983

A rare cause of AA amyloidosis: Hereditary epidermolysis bullosa

First author:  Chaabouni et al

Review: Néphrologie et thérapeutique

Reference :  DOI : 10.1016/j.nephro.2021.08.005

Link to article: https://doi.org/10.1016/j.nephro.2021.08.005

Introduction:

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disorder transmitted in an autosomal recessive manner. It is characterized by skin and mucosal fragility, leading to blister formation after minor trauma, with a cleavage occurring beneath the epidermis, under the lamina densa. It is associated with mutations in the COL7A1 gene, which encodes collagen VII, the main component of anchoring fibrils. RDEB manifests at birth with widespread skin blisters and erosions, accompanied by severe mucosal involvement.

The prognosis for RDEB is poor, and death usually occurs within the first three decades of life. Multiple complications arise, mainly malnutrition, recurrent infections, and the malignant transformation of chronic skin lesions into squamous cell carcinoma. AA amyloidosis, primarily affecting the kidneys, is a rare systemic complication of RDEB. In this article, the authors report two cases of renal AA amyloidosis in Tunisian patients with RDEB.

Case Reports:

Case 1:

The patient was a man born from a consanguineous marriage, diagnosed with RDEB. He presented with generalized blistering lesions since birth (Fig. 1). Severe mucosal involvement of the oral cavity was noted, though the scalp was unaffected. Electron microscopy of a skin biopsy revealed alterations in the anchoring fibrils. A mutation (p.R2063W/p.R2063W) in the COL7A1 gene was identified through Sanger sequencing. At the age of 38, the patient developed progressive lower limb edema that was white, soft, and pitting, which had appeared over two months, along with asthenia and oliguria. His blood pressure and cardiopulmonary examination were normal. Laboratory tests revealed hypochromic microcytic anemia (hemoglobin: 9 g/dL), end-stage renal disease, hypoproteinemia (46 g/L), and profound hypoalbuminemia (9.7 g/L). Urinalysis showed heavy proteinuria (4 g/24h) and hematuria (2+).

Given this nephrotic syndrome, renal AA amyloidosis was diagnosed based on the presence of amyloid deposits in the glomeruli and along the vascular walls, confirmed by renal biopsy. Hemodialysis was recommended but refused by the patient, who passed away two months later.

Case 2:

A 28-year-old woman, born from a consanguineous marriage, presented with pitting lower limb edema that had been present for one month. She had been followed for RDEB since birth. The skin examination revealed blistering lesions and post-blister erosions on the extremities and back. The healing process was slow, resulting in atrophic scarring without milia formation. There was no syndactyly.

Mucosal involvement included oligodontia (Fig. 2), and additional findings included toenail anonychia and cicatricial alopecia. Sequencing of the COL7A1 gene revealed a mutation (p.G1483D/pG1483D). Laboratory tests showed severe hypochromic microcytic anemia (hemoglobin: 7 g/dL), hypoproteinemia (42 g/L), hypoalbuminemia (18 g/L), and proteinuria (8 g/24h). Renal and hepatic function were normal.

A biopsy of the accessory salivary glands confirmed the presence of amyloid deposits.

Two months after diagnosis, the patient was admitted for a urinary tract infection caused by Escherichia coli. Her renal function rapidly deteriorated, with a creatinine clearance of 15 mL/min. The patient died a few days later from septic shock.

Discussion:

AA amyloidosis secondary to epidermolysis bullosa mainly complicates severe forms such as RDEB, due to chronic inflammation from recurrent skin infections.

Aside from hydronephrosis secondary to stenosing uropathies, other main causes of renal involvement in RDEB include post-infectious glomerulonephritis and mesangial glomerulonephritis with immunoglobulin A (IgA) deposition.

AA amyloidosis represents a severe, often fatal complication of RDEB.

Conclusion:

These two cases of AA amyloidosis in RDEB highlight the severity of this often fatal complication. Annual screening for proteinuria would allow for early diagnosis, and new treatments could improve the prognosis in these vulnerable patients.

Une cause rare et très sévère de l’amylose AA _ Les épidermolyses bulleuses héréditaires.p

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Fig. 1. Des lésions bulleuses et des érosions post-bulleuses du tronc chez notre premier patient (a), avec une syndactylie (b).

Authors	Year of publication	Number of cases	Amyloidosis-related disorders	Hemodialysis	Evolution
Chaabouni et al (1)	2021	2	Renal	Yes	Death of the 2 reported cases
Kaneko et al(2)	2000	7	Renal	Yes	Death of index case
Bourke et al(3)	1995	2	Renal	Unspecified	Death
Pinarbasi et al (4)	2019	1	Renal	Unspecified	Death
S yi (5)	1988	1	Renal	Unspecified	Death

References:

1. Chaabouni R, Amouri M, Chaari C, Bouattour Y, Sellami K, Bahloul Z, et al. Une cause rare de l’amylose AA : les épidermolyses bulleuses héréditaires. Néphrologie & Thérapeutique [Internet]. avr 2022 [cité 8 sept 2024];18(2):136‑9. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S1769725521005319

2. Kaneko K, Kakuta M, Ohtomo Y, Shimizu T, Yamashiro Y, Ogawa H, et al. Renal Amyloidosis in Recessive Dystrophic Epidermolysis bullosa. Dermatology [Internet]. 2000 [cité 8 sept 2024];200(3):209‑12. Disponible sur: https://karger.com/DRM/article/doi/10.1159/000018384

3. Bourke JF, Browne G, Gaffney EF, Young M. Fatal systemic amyloidosis (AA type) in two sisters with dystrophic epidermolysis bullosa. Journal of the American Academy of Dermatology [Internet]. août 1995 [cité 8 sept 2024];33(2):370‑2. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/0190962295914366

4. Pinarbasi A, Dursun I, Daldaban B, Günay N, Çiçek S, Şahin N, et al. Epidermolysis bullosa complicated with nephrotic syndrome due to AA amyloidosis: A case report and brief review of literature. Saudi J Kidney Dis Transpl [Internet]. 2019 [cité 8 sept 2024];30(6):1450. Disponible sur: https://journals.lww.com/10.4103/1319-2442.275492

5. Yi S, Naito M, Takahashi K, Nogami R, Maekawa Y, Arao T. Complicating systemic amyloidosis in dystrophic epidermolysis bullosa, recessive type. Pathology [Internet]. 1988 [cité 8 sept 2024];20(2):184‑7. Disponible sur: https://linkinghub.elsevier.com/retrieve/pii/S003130251636634X

VEXAS syndrome as a new differential diagnosis of late onset spondyloarthritis

Article title: Syndrome VEXAS comme nouveau diagnostic différentiel de la spondyloarthrite du sujet âgé

First author: Jain H

Journal: MEDITERRANEAN JOURNAL OF RHEUMATOLOGY

Link to the article: https://pubmed.ncbi.nlm.nih.gov/39463879/

Author of the abstract: Philippe Mertz

VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is an autoinflammatory disease associated with somatic mutations in the UBA1 gene, mainly observed in people over the age of 50. This gene encodes a key enzyme in the ubiquitination process, whose dysfunction leads to the activation of several inflammatory pathways. Signs suggestive of VEXAS syndrome include macrocytic anemia, neutrophilic dermatoses (such as Sweet's syndrome), pulmonary and ophthalmological involvement, thrombosis, and various rheumatological manifestations. The latter often present as arthralgia or mono-, oligo-, or polyarthritis.

Spondyloarthritis in older individuals is a rare condition that can be axial and/or peripheral, with an inflammatory component that is often more pronounced than in younger individuals. It requires the elimination of certain specific differential diagnoses, including microcrystalline rheumatism, rhizomelic pseudo-polyarthritis, giant cell arteritis, and paraneoplastic rheumatism.

The authors report the case of a 67-year-old man living in India with peripheral polyarthritis associated with chronic inflammatory low back pain. Skin lesions had also been observed for a month, and biopsy revealed neutrophilic dermatosis, which responded well to corticosteroid therapy. Rheumatological tests showed the presence of HLA B27, active bilateral sacroiliitis on MRI, synovitis of the wrists, and bilateral retrocalcaneal bursitis. Initial treatment with sulfasalazine and NSAIDs failed, and the introduction of methotrexate at 15 mg/week was also ineffective. Further investigations revealed macrocytic anemia (Hb = 8.3 g/dL, MCV = 106 fL) associated with a biological inflammatory syndrome (CRP = 38 mg/L). These abnormalities led to Sanger sequencing of the UBA1 gene, confirming the diagnosis of VEXAS syndrome due to the p.Met41Leu mutation. Corticosteroid therapy combined with sulfasalazine at 1 mg/day controlled the joint symptoms.

Two other cases of spondyloarthritis in older patients associated with VEXAS syndrome have been reported:

A 57-year-old man living in France, presenting with a similar clinical picture, including peripheral polyarthritis, bilateral sacroiliitis, HLA-B27 positivity, and biological inflammatory syndrome (2). When the first inflammatory symptoms appeared at the age of 57 in 2010, treatment with anti-TNF alpha initially provided good control of the symptoms. Subsequently, he developed acute anterior uveitis, chondritis of the ear and nose, chronic inflammatory bowel disease (IBD), and neutrophilic dermatosis. Several lines of treatment were attempted without lasting success, including methotrexate, azathioprine, cyclophosphamide, baricitinib, infliximab, tocilizumab, anakinra, and ustekinumab. Finally, a combination treatment of intravenous immunoglobulins (2 g/kg every 4 weeks) and secukinumab (300 mg every 4 weeks) proved effective. The diagnosis of VEXAS syndrome associated with the Met41Thr mutation was made retrospectively in 2020.

A 74-year-old Caucasian man with a recent history of venous thrombosis in the lower limbs presented with inflammatory low back pain with bilateral sacroiliitis on MRI, macrocytic anemia (Hb = 8.8 g/dL and MCV = 101 fL), but without significant biological inflammatory syndrome (3). He subsequently developed progressive anemia (Hb = 8.5 g/dL and MCV = 100 fL), purpura of the lower limbs, erythema nodosum, and chondritis of the ear. He was diagnosed with VEXAS syndrome associated with the Met41Thr mutation of the UBA1 gene. After several treatments failed, including tocilizumab complicated by abscessed diverticulitis, azacitidine at the standard dose of 75 mg/m²/day led to a significant reduction in corticosteroid therapy (from 40 mg/day to 5 mg/day) and clinical improvement of symptoms.

The manifestations of VEXAS syndrome are varied and still poorly defined. It appears to be one of the new differential diagnoses to consider in cases of spondyloarthritis in older patients, particularly those aged 50 and over, given the age of onset of VEXAS syndrome and especially in the presence of a biological inflammatory syndrome, hematological abnormalities with associated anemia, particularly macrocytic anemia, or other suggestive findings such as neutrophilic dermatosis. An atypical history or the appearance of new extra-rheumatological symptoms, such as venous thrombosis, inflammatory dermatoses (particularly neutrophilic), chondritis, or pulmonary involvement, should also point to this diagnosis. In addition, resistance to initial treatment with NSAIDs may be a warning sign, especially since the hematological abnormalities associated with VEXAS syndrome may appear secondarily.

REFERENCES

Jain H, Roy D, Mavidi S, Haldar S, Mondal S, Bhattacharya P, et al. Elderly Onset Spondyloarthropathy and VEXAS Syndrome: A Case Report. Mediterr J Rheumatol. 2024 Sep;35(3):490–3.

Magnol M, Couvaras L, Degboé Y, Delabesse E, Bulai-Livideanu C, Ruyssen-Witrand A, et al. VEXAS syndrome in a patient with previous spondyloarthritis with a favourable response to intravenous immunoglobulin and anti-IL17 therapy. Rheumatology (Oxford). 2021 Sep 1;60(9):e314–5.

Pereira da Costa R, Sapinho G, Bandeira M, Infante J, Marques T, Mimoso Santos C, et al. Case report: VEXAS syndrome: an atypical indolent presentation as sacroiliitis with molecular response to azacitidine. Front Immunol. 2024;15:1403808.

Syndrome VEXAS comme nouveau diagnostic différentiel de la spondyloarthrite du sujet âgé.p

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