Manuscript # BOLI2623 revised

Farber lipogranulomatosis with predominant joint involvement mimicking juvenile idiopathic arthritis.

Mikhail M. Kostik1§, Irina A. Chikova1, Vladislav V. Avramenko1, Laly I. Vasyakina2, Emmanuelle Le Trionnaire3, Vyacheslav G. Chasnyk1, Thierry Levade3

Supplemental material

Figure.A) General view of patient with Farber lipogranulomatosis, B) Hand involvement, C) Granulomatous arthritis of wrist, D) Hand X-ray: severe osteoporosis, bone destruction, joint subluxation and joint ankylosing, E) Subcutaneous granuloma in sacral spine, F) Tongue granulomas.

Table 1. Results of hematological and biochemical assessment.

Hematology / Normal range
Hb / 98* / 110-165 g/l
RBC / 4.0 / 3.8-5.8 1012/l
Ht / 267 / 350-500
Plt / 429 / 180-400 109/l
WBC / 6.3 / 4-10 109/l
- bands / 4 / %
- segments / 54 / %
- lymphocytes / 39 / %
- monocytes / 1 / %
- eosinophils / 2 / %
ESR, Westergren / 33* / mm/h
Reticulocytes / 0.3 / 0.2-1.0%
______
Biochemistry
Serum protein / 68 / 65g/l
Albumin / 38.2 / 55%
α1-globulins / 3.8 / 4%
α2-globulins / 13.3 / 10%
β-globulins / 14.6 / 14%
γ-globulins / 29.7* / 14%
СRP / 40* / <6 mg/l
ALT / 22 / 42 U/l
AST / 53* / <38 U/l
Bilirubin total / 5.3 / <21 micromol/l
Glucose / 4.4 / 5.5 mmol/l
Urea / 6.4 / <6.4 mmol/l
Uric acid / 0.22 / 0.14-0,23 mmol/l
Cholesterol / 3.8 / 4.8 mmol/l
Triglycerides / 0.62 / 0.36-1.29 mmol/l
HDL / 0.77* / 1.42 mmol/l
LDL / 2.64 / 3 mmol/l
Serum creatinine / 0.027 / 0.088 mmol/l
CK / 51 / 170 U/l
LDH / 872* / 450 U/l
γ-GTP / 63* / 39 U/l
Ferritin / 94 / 7-140 ng/ml
Fe / 3.7* / 8.8-27 micromol/l
Transferin / 42.3 / 45-75 micromol/l
K+ / 4.7 / 4.5-5.5 mmol/l
Na+ / 138 / 132-142 mmol/l
Cl- / 104 / 95-110 mmol/l
Ca total / 2.41 / 2.5 mmol/l
Inorganic Phosphorus / 1.66 / 0.8-2.3 mmol/l

Abbreviations: Hb, hemoglobin; RBC, red blood cells; Ht, hematocrit; Plt, platelets; WBC, white blood cells; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HDL, high-density lipoproteins; LDL, low-density lipoproteins; CK, creatine kinase; LDH, lactate dehydrogenase; γ-GTP, gamma-glutamyl transpeptidase; Fe, iron.
Table 2. Immunological status of patient with Farber lipogranulomatosis.

Parameters / Patient / Normal values
Lymphocytes
CD3+ (T lymphocytes)
CD3+CD(16+56) + (TNK-cells)
CD3+CD4+ (T helpers)
CD3+CD8+ (T-killers)
CD4+CD8+ (double-positive T lymphocytes)
CD3-CD8+ (activated NK-cells)
CD4/CD8
CD3-CD(16+56)+NK-cells
CD19+ (B-lymphocytes)
CD25+(IL-2 receptor)
HLA DR+
CD(16+56)+HLA DR+ (activated NK-cells)
CD95+
CD19+CD5+ / (%)
69
0.2
45*
20*
0.2
9.5*
2.25*
15
15
11*
16
1.4*
3
7.5 / (%)
66-76
0.1-8.0
33-41
23-40
0.1-1.5
1.5-6
1.0-1.4
9-16
12-22
1.5-6
12-24
0-0.8
2-5
4-10
SerumImmunoglobulins
Immunoglobulin А (g/l)
Immunoglobulin М (g/l)
ImmunoglobulinG (g/l)
Immunoglobulin Е (g/l) / 2,2
1,6*
18,8*
45 / 0,7-2,22
0,8-1,5
7,3-13,5
45-60
Circulating Immune Complexes
-High molecular weight
-Medium molecular weight
-Low molecular weight / units
21
53
326* / units
<50
<60
<130
Spontaneus production# / Stimulated production# / Serum level
Patient / Normal values / Patient / Normal values / Patient / Normal values
Interleukins
IL-1β
IL-6
TNF-α / (pg/ml)
7
84*
5 / (pg/ml)
0-50
0-50
0-70 / (pg/ml)
3*
617
193 / (pg/ml)
1000-5000
1000-3000
500-1500 / (pg/ml)
147*
2
6 / (pg/ml)
0-50
0-50
0-70

# Spontaneus and stimulated production was measured in supernatants of leukocytes before and after pyrogenal stimulation after 24 hours incubation. Abbreviations: TNK, T lymphocytes with NK cell markers; NK, natural killers; IL-1β, interleukin-1β; IL-6, interleukin-6; TNF-α, tumor necrosis factor α.

Table 2 showssigns of immune system activation: high level of NK and CD25-positive cells, increased levels of immunoglobulin level and circulating immune complexes, increased number of T-helpers and decreased number of T-suppressors. The elevation of IL-1β accompanied with high ESR, CRP and LDH could explain some mechanisms of uncontrolled inflammation in Farber disease due to activation of innate immunity (Dinarello 2011). Similar changes could be seen in hereditary autoinflammatory syndromesin which uncontrolled inflammation with bone and joint involvement is typical (Martinon et al 2002, Lamkanfi et al 2011). Farber disease could therefore be included in the group of autoinflammatory diseases in which IL-1β plays a crucial role (IL-1β-dependent conditions). In addition, a number of studies have already reported the correlation between ceramide accumulation and production/secretion of inflammatory cytokines,including IL-1β (Park 2006, Nixon 2009).

Additional references

1. Dinarello CA (2011) A clinical perspective of IL-1beta as the gatekeeperof inflammation. Eur J Immunol 41: 1203–1217.

2. Lamkanfi M, Walle LV, Kanneganti TD (2011) Deregulated inflammasomesignaling in disease. Immunol. Rev. 243: 163–173.

3. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417-26.

4. Nixon GF(2009)Sphingolipids in inflammation: pathologicalimplications and potential therapeutic targets. Brit. J. Pharmacol. 158: 982–993.

5. Park JH, Schuchman EH (2006)Acid ceramidase and human disease.Biochim Biophys Acta1758(12):2133-8.