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

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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

Anti-proinflammatory cytokine biotherapy can prevent the progression of AA amyloidosis to end-stage renal disease.

First author: Kvacskay P

Revue : Annals of Rheumatic disease

Reference:  PMID: 38653531 ; DOI: 10.1136/ard-2023-225114

Lien vers pubmed: https://pubmed.ncbi.nlm.nih.gov/38653531/

Introduction:

AA amyloidosis (AA) can be the consequence of any chronic inflammatory disease. AA is associated with chronic inflammatory diseases (cid+AA), autoinflammatory syndromes (auto+AA) or AA of unknown origin or idiopathic AA (idio+AA). The major organ manifestation is renal AA that can progress to end-stage renal disease (ESRD) and multiple organ failure.

Materials and methods:

This study is a monocentric retrospective analysis of the renal outcome and survival of patients with cid+AA (n=34), auto+AA (n=24) and idio+AA (n=25) who were treated with cytokine-inhibiting biological disease-modifying antirheumatic drugs (bDMARDs).

Results

83 patients with renal AA amyloidosis were identified and followed for a mean observation period of 4.82 years.

The patients were 34 with cid+AA (40.5%), including 18 with rheumatoid arthritis and 8 with chronic inflammatory bowel disease; 25 with idio+AA (30.5%) and 24 with auto+AA (29%), including 22 with familial Mediterranean fever and 2 with cryopyrinopathies.

Levels of C-reactive protein (CRP), serum amyloid A protein (SAA) and proteinuria were significantly reduced under treatment with biotherapy.

With biotherapy, progression to ESRD was prevented in 88% of patients in the auto+AA group, 81% in the idio+AA group and 60% in the cid+AA group during the study period.

Thirty-four patients received tocilizumab in the cid+AA (n=18) and idio+AA (n=16) arms. Tocilizumab was more effective in reducing CRP and progression to ESRD and death than other biotherapies. No patient taking tocilizumab during the study period died.

Patients with autoinflammatory diseases were excluded from this analysis with tocilizumab as this biotherapy is not indicated for inflammatory diseases.

Conclusion

Anti-proinflammatory cytokine biotherapies reduce systemic inflammation in various diseases associated with the development of AA amyloidosis, leading to a reduction in proteinuria and prevention of ESRD.

In this retrospective series, tocilizumab tested in 34 patients with AA amyloidosis complicating chronic or idiopathic inflammatory disease was more effective than other biotherapies in controlling systemic inflammation, leading to improved renal and overall survival in these patients.

Figures

Figure 1. Serum biomarkers and proteinuria are analysed in subgroups of AA patients with chronic inflammatory disease cid+AA (cid+AA), autoinflammatory disease auto+AA (auto+AA) and idiopathic disease (idio+AA).

Biotherapy was initiated at the first visit (baseline) and compared with the last documented visit 4 to 6 years later. CRP (A), SAA (B), serum creatinine (C), sample proteinuria (D), serum albumin (E), total serum protein (F), serum IgG (G) and NT-BNP (H) were analysed at the first and last visits.

Figure 2: Patients treated with Tocilizumab (TOC) were compared with other biotherapies.

(A): Patients with cid+AA (cid+AA) and idio+AA were followed every 6 months until the last visit.

(B) and (C): Analyses of cid+AA (cid+AA) and idio+AA subgroups are shown. (D) Across the cohort tocilizumab (TOC) prevented progression of AA to other organs and death (D).

bDMARD can prevent the progression of AA

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Development and Validation of Staging Systems for AA Amyloidosis

First author:  Basset et al

Review:  Journal of the American Society of Nephrology

Reference :  DOI :   10.1681/ASN.0000000000000339

Link to article:  https://pubmed.ncbi.nlm.nih.gov/38512269/

Introduction:

Inflammatory amyloidosis is a rare disease secondary to the deposition of serum amyloid A (SAA) protein in the form of insoluble amyloid fibrils, causing predominantly renal damage and dysfunction that may progress to end-stage renal disease requiring dialysis. Renal involvement is almost constant in all cases of AA amyloidosis at the time of diagnosis, while cardiac involvement is uncommon. Unlike the more common forms of systemic amyloidosis, particularly AL and ATTR, AA amyloidosis has not yet been the subject of prospective studies.

Thanks to their ability to accurately predict prognosis without the need for invasive and expensive tests, stratification systems based on biomarkers are playing a well-established role in the management of patients with systemic amyloidosis. For example, stratification systems for overall survival and renal failure have been validated for AL amyloidosis. More recently, two overall survival stratification systems have been validated for transthyretin amyloidosis (ATTR). However, AA amyloidosis has not yet had a validated system for stratifying the risk of renal progression of the disease. In this study, the authors developed and validated a stratification system for overall survival and renal failure in patients with newly diagnosed AA amyloidosis.

Methods :

Patients included.

The databases of the Amyloidosis Research and Treatment Centre in Pavia, Italy, and the Amyloidosis Centre in Heidelberg, Germany, were used. Four hundred and seventy-six consecutive patients with newly diagnosed AA amyloidosis, including 233 in Pavia between 1991 and 2020 and 243 in Heidelberg between 1975 and 2020, were included in the study.

In the absence of a specific consensus on the definition of organ involvement in AA amyloidosis, the authors chose to use the criteria for organ involvement in AL amyloidosis: glomerular filtration rate (eGFR), B-type natriuretic peptide (BNP) and N-terminal BNP (NT-proBNP).

The Italian cohort was used as the test population and the German series as the validation cohort in the analysis.

Statistical analysis

ROC analyses based on survival, death and dialysis of patients with AA amyloidosis at 24 months were used to identify biomarker thresholds, which according to the Youden index, best discriminate between overall survival and renal failure. Median follow-up was estimated using the inverse Kaplan-Meier method. Overall survival was calculated from diagnosis to death (event) or last contact with the living patient.

The stratification system developed in the Pavia cohort was applied to the Heidelberg cohort. Given the good discrimination and calibration, the authors combined the two cohorts for subsequent analyses, in order to make effective use of the information contained in the risk categories and to increase the precision of the associated HR estimates.

Results:

A total of 476 patients were evaluated during the study period (233 in Pavia and 243 in Heidelberg), most of whom (>95%) were diagnosed after 2000 (Table 1). Renal involvement was present in 95% of cases; 33 Italian (14%) and 47 German (19%) patients were already on dialysis at the time of diagnosis respectively.

Differences were observed between the two cohorts: serum albumin levels were higher and German patients were younger than Italian patients. Differences were also observed in the underlying causes of chronic inflammation, with a higher proportion of recurrent infections and idiopathic AA in Italy and more autoinflammatory diseases in Germany. t .

The median follow-up of patients was 67 months in Italy and 36 months in Germany. In the Italian cohort, 58 (25%) patients died and 51 (21%) in the German cohort. No difference in overall survival was observed between the two cohorts (Log-rank test p=0.28).

Among patients who were not on dialysis at the time of diagnosis, 68 (32%) progressed to end-stage renal disease in the Pavia group and 56 (29%) in the Heidelberg cohort.

Identification of biomarker thresholds that best discriminate between overall survival and renal failure

The most discriminating thresholds for overall survival at 24 months in the Pavie test cohort were

- eGFR 45 ml/min/1.73 m2

- 3.0 g/dL for serum albumin

- 40 mg/L for SAA

- 130 ng/L for BNP

- 1000 ng/L for NT-proBNP

The most discriminating thresholds for dialysis at 24 months were

- GFR at 35 ml/min/1.73 m2

- 3.0 g/dL for serum albumin

- 25 mg/L for SAA

- 3 g/24h for 24-hour proteinuria

Prediction of overall survival and stratification system (Table 2)

The stratification system calculated as the sum of the simplified coefficients ranged from 0 to 3. Because of the low number of deaths in certain categories, the authors grouped score 0 with score 1 (low-risk category). This stratification system identified three groups of patients with significantly different survival.

Overall survival at 5 years was 94% (95% CI: 87-98%) in the low-risk category, 80% (95% CI: 62-90%) in the intermediate-risk category and 46% (95% CI: 21-68%) in the high-risk category.

Discussion and conclusion:

This is the first study to propose a stratification system based on non-invasive biomarkers for overall survival and renal failure in AA amyloidosis.

Older age at diagnosis, 24h proteinuria, proteinuria/creatinuria ratio

were confirmed as poor prognostic factors for survival and progression to renal failure.

In conclusion, the authors propose these biomarkers for stratifying overall survival and renal failure with the aim of improving the management of patients with AA amyloidosis by identifying the most severe cases.