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. 2021 Apr 9:8:656667.
doi: 10.3389/fmed.2021.656667. eCollection 2021.

Synovial Immunohistological Biomarkers of the Classification of Undifferentiated Arthritis Evolving to Rheumatoid or Psoriatic Arthritis

Andrea Cuervo  1 , Raquel Celis  1 , Antonio Julià  2 , Alicia Usategui  3 , Regina Faré  3 , Julio Ramírez  1 , Ana Belen Azuaga  1 , Andrés Lorenzo  1   4 , Raimon Sanmartí  1 , José L Pablos  3 , Juan D Cañete  1
Affiliations

Synovial Immunohistological Biomarkers of the Classification of Undifferentiated Arthritis Evolving to Rheumatoid or Psoriatic Arthritis

Andrea Cuervo et al. Front Med (Lausanne). .

Abstract

Background: Undifferentiated arthritis (UA) is defined as an inflammatory arthritis that does not fulfill criteria for a definite diagnosis. Delay in reaching a specific diagnostic and therapy may lead to impaired functional outcomes. Our aim was to identify synovial biomarkers associated with definitive diagnostic classification in patients with UA. Methods: DMARD-naïve UA patients with available initial synovial tissue (ST) and a final diagnosis of rheumatoid arthritis (RA) or psoriatic arthritis (PsA) during follow-up were included and compared with patients with well-defined disease (RA or PsA). Clinical, arthroscopic, and pathological data were compared between groups. Pathology included quantitative immunohistochemical (IHC) analysis of cell types and human interferon-regulated MxA. Principal component analysis (PCA) was performed to extract disease patterns. Results: One hundred and five patients were included: 31 patients with DMARD-naïve UA (19 evolving to RA and 12 to PsA during a median follow up of 7 years), 39 with established RA, and 35 with established PsA. ST from the UA group showed higher macrophage density compared with the established RA and PsA groups. Patients with UA evolving to RA (UA-RA) showed higher MxA expression and CD3+ T-cell density compared with established RA. UA patients evolving to PsA (UA-PsA) showed increased vascularity and lining synovial fibroblast density compared with established PsA. Synovitis of UA-PsA patients showed more mast cells and lining fibroblasts compared with UA-RA. No between-group differences in local or systemic inflammation markers were found. Conclusions: Our results show differences in the cellular composition of UA synovium compared with RA and PsA, with higher density of the cellular infiltrate in the UA groups. Initial expression of the interferon inducible gene MxA could be a biomarker of progression to RA, while higher mast cell and fibroblastic density may be associated with PsA progression.

Keywords: biomarkers; psoriatic arthritis; rheumatoid arthritis; synovitis; undifferentiated arthritis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Principal Component analysis (PCA). Distribution of samples according to the PC1 and PC2. The variables included were those that had no missing values or those with as maximum 1 missing value (which we impute): CD3+ T-cells, CD20+ B-cells, CD79+ B-cells, CD138+ plasma-cells, CD31+ endothelial cells, CD68+ lining macrophages, CD68+ sublining, CD79+ B-cells, CD15+ neutrophils, and CD117+ mast cells. Reducing the data dimensionality to the main PCs does not show a clear separation between any of the 4 groups of patients.
Figure 2
Figure 2
Characterization of cellular patterns by patient group. Violin plots depicting density distributions of positive cells (in area = 1 mm2), stained with surface protein antibodies and analyzed by immunohistochemitry. Inner boxplots show median, interquartile range, minimum and maximum values of every analyzed surface marker. Undifferentiated Arthitis (UA-RA, UA-PsA) and definite Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) using ANOVA-test, p-values between different groups are depicted for each marker.
Figure 3
Figure 3
Immunostaining of cellular infiltrate in synovial membrane of UA-RA, UA-PsA, RA and PsA patients. (A) Adaptive immune cells (CD3, CD20, CD79, and CD138, 20 × ); (B) innate immune cells (CD68, CD15, and CD117, 20 × ); and (C) stroma cells (CD31, 10 × ) and Immuno-fluorescence labeling of fibroblast Hsp47+ (red) in sections from synovial tissue. DAPI (blue) nuclear counterstained; original magnification 20 ×. RA, rheumatoid arthritis; PsA, psoriatic arthritis; UA, undifferentiated arthritis evolving to RA (UA-RA) or PsA (UA-PsA).
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