Could tocilizumab be used in familial Mediterranean fever? A systematic review

First author : P. Mertz

Review: Rheumatology

Link to article: https://doi.org/10.1093/rheumatology/keae338

Could tocilizumab be used in Familial Mediterranean Fever ?

Abstract:

Introduction:

Familial Mediterranean Fever (FMF) is the most common monogenic autoinflammatory disease characterized by recurrent fever and serosal inflammation. Although colchicine is the primary treatment, around 10% of FMF patients do not respond to it, necessitating alternative therapies. Biologic treatments, such as IL-1β, TNF-α and IL-6 inhibitors, have been considered. However, the accessibility and cost of IL-1β inhibitors may limit their use in certain regions. Tocilizumab (TCZ), an IL-6 receptor inhibitor, offers an alternative, but its efficacy in FMF is not well-documented.

Results:

After selection, 14 articles were included: two double-blind RCTs, two retrospective studies and 10 case reports. Multicentre double-blind RCTs reported mixed results in FMF patients without AA amyloidosis due to genetic/classification heterogeneity of the available studies, possible misdiagnosed FMF patients and study design. Retrospective studies suggest that TCZ may benefit FMF patients with established renal AA amyloidosis, potentially preventing progression and managing flares more effectively. TCZ showed a safe profile with no specific adverse events, but data on its use during pregnancy or breastfeeding are lacking. There was no available data on the use of TCZ in paediatric FMF.

Conclusion:

This review summarizes the current state of research, safety and efficacy of TCZ in FMF. While IL1β inhibitors remain the first choice for colchicine-resistant or intolerant FMF patients, TCZ might be of interest in some selected FMF patients with established AA amyloidosis and resistance to colchicine and interleukin 1 inhibitors.

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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).

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Frequency of AA amyloidosis has decreased in Behçet’s syndrome: a retrospective study with long-term follow-up and a systematic review: Amyloidosis in Behçet’s syndrome

First author : G Karatemiz

Review : Rheumatology

Reference :  DOI :  doi.org/10.1093/rheumatology/keac223

Link to article https://academic.oup.com/rheumatology/article/62/1/9/6601421

Introduction:

Inflammatory rheumatic diseases are a classic cause of inflammatory amyloidosis (AA). Behçet's disease is a multi-systemic vasculitis that affects vessels of all calibres. Although uncommon in Behçet's disease, AA amyloidosis is at high risk of mortality and is one of the main causes of renal failure in Behçet's disease. The authors' aim was to determine the frequency of AA amyloidosis in patients with Behçet's disease, and identify clinical and therapeutic demographics.

Methods:

Patients with Behçet's disease complicating with AA amyloidosis in Turkey were included. The primary endpoints were end-stage renal disease and death. The prevalence of AA amyloidosis was estimated separately for patients registered between 1976 and 2000 and those registered between 2001 and 2017, to determine whether there was a change in frequency.

A systematic review of the literature on cases of AA amyloidosis complicating Behçet's disease accompanied this study.

Results:

Between 1976 and 2017, a cohort of patients with Behçet's disease (n=9410) was followed of whom, 27 (0.29%) developed AA amyloidosis.

Between 1976 and 2000, a cohort of 3,820 patients with Behçet's disease was followed; 24 patients (0.62%) developed AA amyloidosis.

Between 2001 and 2017, of the 5590 patients followed for Behçet's disease, 3 developed AA amyloidosis (0.054%).

The incidence of AA amyloidosis increased from 0.62% to 0.054% (P < 0.0001).

Co-morbidities that may be associated with amyloidosis were tuberculosis (n= 2), FMF

FMF (n=1) and spondyloarthritis (n=1). MEFV gene sequencing had been performed in 2 patients showing no pathogenic variant, and one of them was heterozygous for the M680I mutation.

Prior to the diagnosis of AA amyloidosis, 19 patients (70%) were on colchicine, 15 patients were on immunosuppressants and 2 on corticosteroids only. At the time of amyloidosis diagnosis, 12 patients were off treatment, 8 were using an immunosuppressant (5 AZA, 2 CYC and 1 MTX), and 2 were using CS only.

Outcome:

Fourteen patients (52%) died after a median follow-up of 3 years (IQR: 7.75), 3 were lost to follow-up and 10 (37%) were still alive after a median follow-up of 11 years

(IQR: 16). The reasons for death were infections in 5 cases, complications related to end-stage renal failure in 5 cases, subarachnoid haemorrhage, gastric adenocarcinoma, cirrhosis associated with amyloidosis and iatrogenic intestinal perforation in one case each. Nine (64%) of the 14 patients who died had developed end-stage renal disease (ESRD).

Overall, 15/27 patients (55.5%) developed ESRD after a median follow-up of 3.5 years (IQR: 5.25) after diagnosis of AA amyloidosis. Five patients underwent renal transplantation.

A systematic review of the literature revealed 82 cases in 42 publications. The main characteristics of the patients were a predominance of males and a high frequency of vascular involvement. One third of patients died within 6 months of diagnosis of AA amyloidosis (table 1).

Discussion and conclusion:

According to the results of this study, the frequency of AA amyloidosis in patients with Behçet's disease appears to be decreasing. Male patients with major organ involvement, particularly vascular involvement, appear to be more likely to develop AA amyloidosis. Although AA amyloidosis rarely complicates Behçet's disease, its occurrence is observed in younger patients and it appears to worsen the overall prognosis of the disease.

Caractéristiques démographiques et cliniques de nos 27 patients BS et de ceux identifiés par la revue systématique

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