Rare Immune System Diseases

**11**

**Chapter 2**

**Abstract**

Felty's Syndrome

large granular lymphocyte leukemia

"Diagnosis and differential diagnosis").

**1. Introduction**

**2. Epidemiology**

Felty's syndrome (FS) is an uncommon subset of seropositive rheumatoid arthritis (RA) complicated by neutropenia with or without splenomegaly. The pathogenesis of neutropenia in FS is still not fully understood, but it is believed that the principal cause is neutrophil survival defect. Autoantibodies against peptidylarginine deiminase type 4 deiminated histones, glucose-6-phosphate isomerase, and eukaryotic elongation factor 1A-1 antigen may contribute to neutropenia development in FS patients. Splenic histology in FS shows non-specific findings and spleen size do not correlate with neutropenia. Cases of T-cell large granular lymphocytic leukemia with low tumor burden in blood and concomitant RA are clinically indistinguishable from FS and present a diagnostic challenge. Examination of T-cell clonality, mutations in signal transducer and activator of transcription 3 gene, and the number of large granular lymphocytes in the blood can establish a correct diagnosis. Optimal approaches to therapy for FS have not been developed, but the use of rituximab seems promising. In this chapter, the epidemiology, pathogenesis, clinical manifestations, differential diagnosis, and treatment options for FS are discussed.

**Keywords:** Felty's syndrome, rheumatoid arthritis, neutropenia, splenomegaly,

In 1924, at Johns Hopkins Hospital, American physician Augustus Felty described five unusual cases with features of chronic arthritis, splenomegaly, and striking leukopenia [1]. In 1932, the eponym "Felty's syndrome (FS)" was first used by Hanrahan and Miller to describe these cases [2]. Currently, FS is considered an uncommon subset of seropositive rheumatoid arthritis (RA) complicated by neutropenia and splenomegaly [3]. Although splenomegaly represents one characteristic of the triad that defines FS, it is not an absolute requirement of FS diagnosis [4, 5]. T-cell large granular lymphocyte (T-LGL) leukemia in the setting of RA is the condition most likely to be confused with FS. Studies on FS should be considered with the caveat that almost all were performed without a study of T-cell clonality and, therefore, could include cases of RA-associated T-LGL leukemia (see

About 1% to 3% of patients with RA develop FS [6]. However, with the evolution of RA pharmacotherapy, the frequency of FS has decreased substantially [7]. The

mean age of the patients is 60 years, with a 1.5:1 female to male ratio [8].

*Vadim Gorodetskiy*

## **Chapter 2** Felty's Syndrome

*Vadim Gorodetskiy*

### **Abstract**

Felty's syndrome (FS) is an uncommon subset of seropositive rheumatoid arthritis (RA) complicated by neutropenia with or without splenomegaly. The pathogenesis of neutropenia in FS is still not fully understood, but it is believed that the principal cause is neutrophil survival defect. Autoantibodies against peptidylarginine deiminase type 4 deiminated histones, glucose-6-phosphate isomerase, and eukaryotic elongation factor 1A-1 antigen may contribute to neutropenia development in FS patients. Splenic histology in FS shows non-specific findings and spleen size do not correlate with neutropenia. Cases of T-cell large granular lymphocytic leukemia with low tumor burden in blood and concomitant RA are clinically indistinguishable from FS and present a diagnostic challenge. Examination of T-cell clonality, mutations in signal transducer and activator of transcription 3 gene, and the number of large granular lymphocytes in the blood can establish a correct diagnosis. Optimal approaches to therapy for FS have not been developed, but the use of rituximab seems promising. In this chapter, the epidemiology, pathogenesis, clinical manifestations, differential diagnosis, and treatment options for FS are discussed.

**Keywords:** Felty's syndrome, rheumatoid arthritis, neutropenia, splenomegaly, large granular lymphocyte leukemia

#### **1. Introduction**

In 1924, at Johns Hopkins Hospital, American physician Augustus Felty described five unusual cases with features of chronic arthritis, splenomegaly, and striking leukopenia [1]. In 1932, the eponym "Felty's syndrome (FS)" was first used by Hanrahan and Miller to describe these cases [2]. Currently, FS is considered an uncommon subset of seropositive rheumatoid arthritis (RA) complicated by neutropenia and splenomegaly [3]. Although splenomegaly represents one characteristic of the triad that defines FS, it is not an absolute requirement of FS diagnosis [4, 5]. T-cell large granular lymphocyte (T-LGL) leukemia in the setting of RA is the condition most likely to be confused with FS. Studies on FS should be considered with the caveat that almost all were performed without a study of T-cell clonality and, therefore, could include cases of RA-associated T-LGL leukemia (see "Diagnosis and differential diagnosis").

#### **2. Epidemiology**

About 1% to 3% of patients with RA develop FS [6]. However, with the evolution of RA pharmacotherapy, the frequency of FS has decreased substantially [7]. The mean age of the patients is 60 years, with a 1.5:1 female to male ratio [8].

#### **3. Pathogenesis**

There is firm evidence that the HLA-DRB1\*04 genotype is a risk factor for FS development [9]. The exact pathophysiological mechanisms leading to development of neutropenia and splenomegaly in FS are unknown. It is believed, though, that neutrophil survival defect is the main cause of neutropenia [8, 10]. Several autoantibodies have been found in the serum of FS patients with higher frequency or at higher titers in comparison with seropositive RA patients without FS, which may contribute to neutropenia development, including:


Autoantibodies against granulocyte colony-stimulating factor (G-CSF) were found in 73% patients with FS [15]. However, given that, in most cases, bone marrow in FS reveals normal myeloid cellularity or myeloid hyperplasia with increased granulopoiesis, relative excess of immature forms, and apparent lack of mature myeloid elements [8], the pathogenetic significance of anti-G-CSF antibodies in neutropenia development in patients with FS is unclear.

Some researchers question the significance of spleen sequestration/destruction in neutropenia pathogenesis [8]. However, neutrophils are found in periarteriolar lymphoid sheaths of the spleen even in patients with severe neutropenia [16]. In addition, removal of the spleen leads to restoration of normal neutrophil counts in most patients with FS.

#### **4. Clinical manifestations**

Clinical manifestations of FS and the frequency of signs/symptoms based on literature data [5, 14, 17–19] are presented in **Table 1**.

FS usually develops 10–15 years after RA presentation [14, 20], but in rare instances, neutropenia and splenomegaly may precede an arthritis history (non-articular Felty's syndrome) [21–24].

The erosive process in FS is typically severe, but this is related to the duration of RA before the onset of neutropenia and splenomegaly [6]. RA with FS is associated with more frequent and severe extra-articular manifestations than RA without FS [14, 20]. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with severe extra-articular manifestations in patients with RA [25]. This is consistent with the finding that the vast majority of patients with FS have high titers of RF [14]. In our cohort of 25 patients with FS with a median duration of RA prior to FS diagnosis of 7 years, erosive arthritis at the time of FS diagnosis was detected in 77% of the patients. RF was within the normal range in only two cases, but the anti-CCP titers in these patients were highly positive [26].

Neutropenia (absolute neutrophil count of less than 1.500–2.000/μL) without a clearly identified cause is required, by definition, for the FS diagnosis. Neutropenia can manifest as increased frequency and severity of bacterial infections. However, despite reduced absolute neutrophil counts, patients with FS can remain free of infectious complications for extended periods of time.

**13**

**Figure 1.**

**Table 1.**

*cords (H&E, ×400).*

*Felty's Syndrome*

Major

Minor

*DOI: http://dx.doi.org/10.5772/intechopen.97080*

**Signs/symptoms Frequency (%)**

Rheumatoid arthritis 100 Neutropenia 100 Splenomegaly 90

Rheumatoid nodules 53–82 Leg ulcers 16–41 Skin pigmentation 5–29 Hepatomegaly/portal hypertension 5–68 Serositis 0–22 Lymphadenopathy 0–34 Neuropathy 11–17 Episcleritis 0–8

*Clinical manifestations of Felty's syndrome and the frequency of signs/symptoms.*

Splenomegaly is present in over 90% of patients with FS, but the spleen size does

*Spleen histological examination in a patient with Felty's syndrome. (A) The spleen shows preservation of the white pulp with prominent germinal centers and lymphocytic infiltration of the red pulp (H&E, ×100). (B) Lymphocytes infiltrate both cords and sinusoids. The infiltration is more prominent within the splenic* 

not correlate with neutropenia [14, 17, 19]. Splenic histology in FS shows nonspecific findings (**Figure 1**). The red pulp shows expanded sinuses as well as the pulp cords, and an increased number of macrophages and plasma cells. The white pulp follicles are usually hyperplastic [18, 27, 28]. It is possible that portal hypertension secondary to nodular regenerative hyperplasia of the liver contributes to spleen

FS should be suspected in a patient with RA, unexplained neutropenia, and splenomegaly. There is a wide range of pathologies in patients with RA that can manifest with neutropenia with or without splenomegaly. FS is a clinical diagnosis,

enlargement in some patients with FS [29].

**5. Diagnosis and differential diagnosis**


#### **Table 1.**

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

contribute to neutropenia development, including:

• circulating immune complexes [14].

neutropenia development in patients with FS is unclear.

literature data [5, 14, 17–19] are presented in **Table 1**.

infectious complications for extended periods of time.

(non-articular Felty's syndrome) [21–24].

deiminase type 4 [11];

most patients with FS.

**4. Clinical manifestations**

There is firm evidence that the HLA-DRB1\*04 genotype is a risk factor for FS development [9]. The exact pathophysiological mechanisms leading to development of neutropenia and splenomegaly in FS are unknown. It is believed, though, that neutrophil survival defect is the main cause of neutropenia [8, 10]. Several autoantibodies have been found in the serum of FS patients with higher frequency or at higher titers in comparison with seropositive RA patients without FS, which may

• autoantibodies to H3, H4, and H2A histones deiminated by peptidylarginine

• autoantibodies against eukaryotic elongation factor 1A-1 antigen [13];

Autoantibodies against granulocyte colony-stimulating factor (G-CSF) were found in 73% patients with FS [15]. However, given that, in most cases, bone marrow in FS reveals normal myeloid cellularity or myeloid hyperplasia with increased granulopoiesis, relative excess of immature forms, and apparent lack of mature myeloid elements [8], the pathogenetic significance of anti-G-CSF antibodies in

Some researchers question the significance of spleen sequestration/destruction in neutropenia pathogenesis [8]. However, neutrophils are found in periarteriolar lymphoid sheaths of the spleen even in patients with severe neutropenia [16]. In addition, removal of the spleen leads to restoration of normal neutrophil counts in

Clinical manifestations of FS and the frequency of signs/symptoms based on

The erosive process in FS is typically severe, but this is related to the duration of RA before the onset of neutropenia and splenomegaly [6]. RA with FS is associated with more frequent and severe extra-articular manifestations than RA without FS [14, 20]. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with severe extra-articular manifestations in patients with RA [25]. This is consistent with the finding that the vast majority of patients with FS have high titers of RF [14]. In our cohort of 25 patients with FS with a median duration of RA prior to FS diagnosis of 7 years, erosive arthritis at the time of FS diagnosis was detected in 77% of the patients. RF was within the normal range in only two cases, but the anti-CCP titers in these patients were highly positive [26]. Neutropenia (absolute neutrophil count of less than 1.500–2.000/μL) without a clearly identified cause is required, by definition, for the FS diagnosis. Neutropenia can manifest as increased frequency and severity of bacterial infections. However, despite reduced absolute neutrophil counts, patients with FS can remain free of

FS usually develops 10–15 years after RA presentation [14, 20], but in rare instances, neutropenia and splenomegaly may precede an arthritis history

• autoantibodies against glucose-6-phosphate isomerase [12];

**3. Pathogenesis**

**12**

*Clinical manifestations of Felty's syndrome and the frequency of signs/symptoms.*

#### **Figure 1.**

*Spleen histological examination in a patient with Felty's syndrome. (A) The spleen shows preservation of the white pulp with prominent germinal centers and lymphocytic infiltration of the red pulp (H&E, ×100). (B) Lymphocytes infiltrate both cords and sinusoids. The infiltration is more prominent within the splenic cords (H&E, ×400).*

Splenomegaly is present in over 90% of patients with FS, but the spleen size does not correlate with neutropenia [14, 17, 19]. Splenic histology in FS shows nonspecific findings (**Figure 1**). The red pulp shows expanded sinuses as well as the pulp cords, and an increased number of macrophages and plasma cells. The white pulp follicles are usually hyperplastic [18, 27, 28]. It is possible that portal hypertension secondary to nodular regenerative hyperplasia of the liver contributes to spleen enlargement in some patients with FS [29].

#### **5. Diagnosis and differential diagnosis**

FS should be suspected in a patient with RA, unexplained neutropenia, and splenomegaly. There is a wide range of pathologies in patients with RA that can manifest with neutropenia with or without splenomegaly. FS is a clinical diagnosis, and there is no specific single diagnostic test to confirm or exclude it; therefore, FS is essentially a diagnosis of exclusion.

Neutropenia caused by drug therapy (drug-induced neutropenia) should be ruled out first. The most important treatment of drug-induced neutropenia is to withdraw the causative drug. The average time for full recovery of the neutrophil count is 9 days (range, 9–24 days) [30]. Methotrexate, cyclophosphamide, azathioprine, sulfasalazine, leflunomide, tocilizumab, tumor necrosis factor (TNF)-alpha antagonists, antimalarial medications, analgesics, and nonsteroidal antiinflammatory drugs are the most common causes of drug-induced neutropenia in patients with RA [28]. It is important to keep in mind that unlike with other drugs, rituximab-induced neutropenia occurs after a median period of 4.5 months (range, 3–6.5 months) after the last rituximab infusion [31].

T-LGL leukemia is a rare type of mature T-cell neoplasm characterized by the clonal expansion of large granular lymphocytes (LGLs) and, in most cases, has indolent clinical course. Typical features of T-LGL leukemia include the increase in the number of peripheral blood LGLs, cytopenia (most commonly neutropenia), and variable splenomegaly. A peculiar feature of T-LGL leukemia is its association with RA, which occurs in 17–28% of patients with T-LGL leukemia [32, 33]. Historically, a definitive diagnosis of T-LGL leukemia required the increase in the number of LGLs in peripheral blood greater than 2 × 109 /L, but it is now recognized that a lower count (range, 0.4–2 × 109 /L) may be compatible with the diagnosis [34–36].

Cases of T-LGL leukemia in the setting of RA (RA-associated T-LGL leukemia) with low LGL count in peripheral blood and concomitant neutropenia are clinically indistinguishable from FS and diagnostically challenging. RA-associated T-LGL leukemia and FS are distinguished in clinical practice by evaluation of rearrangements of the T cell receptor (TCR) gamma and TCR beta genes in the blood and/or in the bone marrow. The monoclonal rearrangements of the TCR genes (T-cell clonality) are present in T-LGL leukemia but not in FS (**Figure 2**) [3, 8, 37]. However,

**Figure 2.**

*Evaluation of T-cell clonality based on rearrangements of the T-cell receptor (TCR) genes. (A) TCR genes show monoclonal rearrangement in T-LGL leukemia. (B) TCR genes show polyclonal rearrangement in Felty's syndrome.*

**15**

*Felty's Syndrome*

with RA.

**6. Management**

controlled trials.

1–2 months.

with RTX.

in FS [45].

*DOI: http://dx.doi.org/10.5772/intechopen.97080*

ficiently specific to distinguish it from FS [8, 26].

there is considerable discussion regarding the significance of dominant T-cell clones as a hallmark of T-cell malignancy because clonal populations of T-cells are observed both in healthy individuals and in exuberant reactive responses [38–43]. Activating somatic mutations in the signal transducer and activator of the transcription 3 (STAT3) gene and an increase in the number of LGLs above 2 × 109

were detected in RA-associated T-LGL leukemia but not in FS (39% vs. 0% and 21% vs. 0%, respectively) [26]. In addition, the expression of the CD57 antigen and the aberrant (diminished or absent) expression of CD5 on cytotoxic CD3 + CD8+ T-lymphocytes are more typical for T-LGL leukemia than in the polyclonal expansion of cytotoxic T-lymphocytes in FS [26]. In contrast, it seems that the current criteria for bone marrow involvement in T-LGL leukemia do not seem to be suf-

Aplastic anemia, myelodysplastic syndromes, or acute leukemia can sometimes present with isolated neutropenia. To rule out these pathologies, a bone marrow examination should be considered. In rare cases, cirrhosis, amyloidosis, lymphomas involving spleen, sarcoidosis, or infections can lead to splenomegaly in patients

In two earlier analyzes of survival in FS, 5-year mortality ranged from 25% to 36% [5, 44]; however, recent data regarding the prognosis of FS are not available. The treatment goal in FS is a reversal of the neutropenia to prevent recurrent bacterial infections and sepsis, which is the leading cause of death in patients with FS. The treatment strategy for FS is not evidence-based because of the lack of

Methotrexate (MTX) is considered the first-line therapy for treatment of FS based on case reports and case series data. Low doses of MTX (up to 25 mg once a week) can improve both joint diseases and neutropenia, usually within

One recent literature review supported the use of rituximab (RTX) as a second-line therapy. A sustained increase in the absolute number of neutrophils was observed in 62.5% of FS patients during the 3 months following one cycle of RTX treatment [45]. The appropriate dosing schedule of RTX for treatment of FS remains uncertain, but most often patients receive two 1000 mg doses separated by 15 days [46]. Some patients had a recurrence of neutropenia after RTX treatment, indicating that in some cases a sustained response may require maintenance therapy

There is very limited evidence regarding the leflunomide efficacy in FS [47]. TNF-alpha inhibitors (adalimumab, ethanercept, and infliximab) are ineffective

Splenectomy maintained normal neutrophil counts in 80% of patients with FS [10]. However, the indications for splenectomy are now limited because of effective

G-CSF can be used for treatment of FS patients with life-threatening infections.

The results of treatment with glucocorticoids (GCs) in patients with FS are variable. GCs can provide a rapid improvement in neutrophil count by stimulating the release of mature cells from the bone marrow and mobilizing them from the marginal pool, thus, creating the effect of increasing their absolute number. However, to achieve a real clinical effect, high doses and prolonged use of GCs may

be required, which increases the risk of infection in patients with FS.

medications and the risk of post-splenectomy sepsis.

/L

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

3–6.5 months) after the last rituximab infusion [31].

number of LGLs in peripheral blood greater than 2 × 109

that a lower count (range, 0.4–2 × 109

[34–36].

is essentially a diagnosis of exclusion.

and there is no specific single diagnostic test to confirm or exclude it; therefore, FS

Neutropenia caused by drug therapy (drug-induced neutropenia) should be ruled out first. The most important treatment of drug-induced neutropenia is to withdraw the causative drug. The average time for full recovery of the neutrophil count is 9 days (range, 9–24 days) [30]. Methotrexate, cyclophosphamide, azathioprine, sulfasalazine, leflunomide, tocilizumab, tumor necrosis factor (TNF)-alpha

inflammatory drugs are the most common causes of drug-induced neutropenia in patients with RA [28]. It is important to keep in mind that unlike with other drugs, rituximab-induced neutropenia occurs after a median period of 4.5 months (range,

T-LGL leukemia is a rare type of mature T-cell neoplasm characterized by the clonal expansion of large granular lymphocytes (LGLs) and, in most cases, has indolent clinical course. Typical features of T-LGL leukemia include the increase in the number of peripheral blood LGLs, cytopenia (most commonly neutropenia), and variable splenomegaly. A peculiar feature of T-LGL leukemia is its association with RA, which occurs in 17–28% of patients with T-LGL leukemia [32, 33]. Historically, a definitive diagnosis of T-LGL leukemia required the increase in the

Cases of T-LGL leukemia in the setting of RA (RA-associated T-LGL leukemia) with low LGL count in peripheral blood and concomitant neutropenia are clinically indistinguishable from FS and diagnostically challenging. RA-associated T-LGL leukemia and FS are distinguished in clinical practice by evaluation of rearrangements of the T cell receptor (TCR) gamma and TCR beta genes in the blood and/or in the bone marrow. The monoclonal rearrangements of the TCR genes (T-cell clonality) are present in T-LGL leukemia but not in FS (**Figure 2**) [3, 8, 37]. However,

*Evaluation of T-cell clonality based on rearrangements of the T-cell receptor (TCR) genes. (A) TCR genes show monoclonal rearrangement in T-LGL leukemia. (B) TCR genes show polyclonal rearrangement in Felty's* 

/L, but it is now recognized

/L) may be compatible with the diagnosis

antagonists, antimalarial medications, analgesics, and nonsteroidal anti-

**14**

**Figure 2.**

*syndrome.*

there is considerable discussion regarding the significance of dominant T-cell clones as a hallmark of T-cell malignancy because clonal populations of T-cells are observed both in healthy individuals and in exuberant reactive responses [38–43]. Activating somatic mutations in the signal transducer and activator of the transcription 3 (STAT3) gene and an increase in the number of LGLs above 2 × 109 /L were detected in RA-associated T-LGL leukemia but not in FS (39% vs. 0% and 21% vs. 0%, respectively) [26]. In addition, the expression of the CD57 antigen and the aberrant (diminished or absent) expression of CD5 on cytotoxic CD3 + CD8+ T-lymphocytes are more typical for T-LGL leukemia than in the polyclonal expansion of cytotoxic T-lymphocytes in FS [26]. In contrast, it seems that the current criteria for bone marrow involvement in T-LGL leukemia do not seem to be sufficiently specific to distinguish it from FS [8, 26].

Aplastic anemia, myelodysplastic syndromes, or acute leukemia can sometimes present with isolated neutropenia. To rule out these pathologies, a bone marrow examination should be considered. In rare cases, cirrhosis, amyloidosis, lymphomas involving spleen, sarcoidosis, or infections can lead to splenomegaly in patients with RA.

#### **6. Management**

In two earlier analyzes of survival in FS, 5-year mortality ranged from 25% to 36% [5, 44]; however, recent data regarding the prognosis of FS are not available. The treatment goal in FS is a reversal of the neutropenia to prevent recurrent bacterial infections and sepsis, which is the leading cause of death in patients with FS. The treatment strategy for FS is not evidence-based because of the lack of controlled trials.

Methotrexate (MTX) is considered the first-line therapy for treatment of FS based on case reports and case series data. Low doses of MTX (up to 25 mg once a week) can improve both joint diseases and neutropenia, usually within 1–2 months.

One recent literature review supported the use of rituximab (RTX) as a second-line therapy. A sustained increase in the absolute number of neutrophils was observed in 62.5% of FS patients during the 3 months following one cycle of RTX treatment [45]. The appropriate dosing schedule of RTX for treatment of FS remains uncertain, but most often patients receive two 1000 mg doses separated by 15 days [46]. Some patients had a recurrence of neutropenia after RTX treatment, indicating that in some cases a sustained response may require maintenance therapy with RTX.

There is very limited evidence regarding the leflunomide efficacy in FS [47]. TNF-alpha inhibitors (adalimumab, ethanercept, and infliximab) are ineffective in FS [45].

Splenectomy maintained normal neutrophil counts in 80% of patients with FS [10]. However, the indications for splenectomy are now limited because of effective medications and the risk of post-splenectomy sepsis.

The results of treatment with glucocorticoids (GCs) in patients with FS are variable. GCs can provide a rapid improvement in neutrophil count by stimulating the release of mature cells from the bone marrow and mobilizing them from the marginal pool, thus, creating the effect of increasing their absolute number. However, to achieve a real clinical effect, high doses and prolonged use of GCs may be required, which increases the risk of infection in patients with FS.

G-CSF can be used for treatment of FS patients with life-threatening infections.

### **7. Conclusion**

Although nearly 100 years have passed since the first description of FS, this pathology remains a mystery in many aspects. The pathogenetic mechanisms underlying neutropenia and spleen enlargement in these patients are poorly understood. Optimal approaches to therapy for this rare disorder have not been developed, but the use of rituximab seems promising.

#### **Acknowledgements**

I would like to thank Editage (www.editage.com) for English language editing.

### **Conflict of interest**

The author declares no conflict of interest.

### **Author details**

Vadim Gorodetskiy

Department of Intensive Methods of Therapy, V.A. Nasonova Research Institute of Rheumatology, Moscow, Russia

\*Address all correspondence to: gorodetskiyblood@mail.ru

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**17**

*Felty's Syndrome*

**References**

1924; 35:16-20

1932; 99:1247-1252

1977;141:156-162

[3] Balint GP, Balint PV.

Felty's syndrome. Best Pract Res Clin Rheumatol. 2004;18,631-645. DOI:10.1016/j.berh.2004.05.002

[4] Spivak JL. Felty's syndrome: an analytical review. Johns Hopkins Med J.

Goulding N, James I, Ahern MJ, Watt I, Sansom D. The Felty syndrome: a casematched study of clinical manifestations and outcome, serologic features, and immunogenetic associations. Medicine

[5] Campion G, Maddison PJ,

(Baltimore). 1990;69:69-80

1991;18:1163-1167

rheumatology/keq135

[8] Burks EJ, Loughran TP Jr.

DOI: 10.1016/j.blre.2006.01.003

[9] Turesson C, Schaid DJ,

Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome. Blood Rev. 2006;20:245-266.

Weyand CM, Jacobsson LT, Goronzy JJ, Petersson IF, Sturfelt G, Nyhäll-Wåhlin BM, Truedsson L, Dechant SA, Matteson EL.

[6] Sibley JT, Haga M, Visram DA, Mitchell DM. The clinical course of Felty's syndrome compared to matched controls. J. Rheumatol.

[7] Bartels CM, Bell CL, Shinki K, Rosenthal A, Bridges AJ. Changing trends in serious extra-articular manifestations of rheumatoid arthritis among United State veterans over 20 years. Rheumatology (Oxford). 2010;49:1670-1675. DOI: 10.1093/

*DOI: http://dx.doi.org/10.5772/intechopen.97080*

The impact of HLA-DRB1 genes on extra-articular disease manifestations in rheumatoid arthritis. Arthritis Res Ther. 2005;7:R1386–R1393. DOI:

[10] Rashba EJ, Rowe JM, Packman CH. Treatment of the neutropenia of Felty syndrome. Blood Rev. 1996;10:177-184.

DOI: 10.1016/s0268-960x(96)

[12] van Gaalen FA, Toes RE,

of autoantibodies to glucose-6-

10.1002/art.20028

pnas.97.16.9234

[14] Goldberg J, Pinals RS. Felty syndrome. Semin Arthritis Rheum. 1980;10:52-65. DOI: 10.1016/0049-0172(80)90014-1

against granulocyte colony-

Ditzel HJ, Schaller M, Breedveld FC, Verweij CL, Huizinga TW. Association

[13] Ditzel HJ, Masaki Y, Nielsen H, Farnaes L, Burton DR. Cloning and expression of a novel human antibodyantigen pair associated with Felty's syndrome. Proc Natl Acad Sci U S A. 2000;97:9234-9239. DOI: 10.1073/

[15] Hellmich B, Csernok E, Schatz H, Gross WL, Schnabel A. Autoantibodies

stimulating factor in Felty's syndrome and neutropenic systemic lupus erythematosus. Arthritis Rheum.

phosphate isomerase with extraarticular complications in rheumatoid arthritis. Arthritis Rheum. 2004;50:395-399. DOI:

[11] Dwivedi N, Upadhyay J, Neeli I, Khan S, Pattanaik D, Myers L, Kirou KA, Hellmich B, Knuckley B, Thompson PR, Crow MK, Mikuls TR, Csernok E, Radic M. Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps. Arthritis Rheum. 2012;64:982-992. DOI: 10.1002/

10.1186/ar1837

90024-7

art.33432

[1] Felty AR. Chronic arthritis in the adult associated with splenomegaly and leukopenia. Bull Johns Hopkins Hosp.

[2] Hanrahan EM, Miller SR. Effect of splenectomy in Felty's syndrome. JAMA.

### **References**

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

developed, but the use of rituximab seems promising.

The author declares no conflict of interest.

Although nearly 100 years have passed since the first description of FS, this pathology remains a mystery in many aspects. The pathogenetic mechanisms underlying neutropenia and spleen enlargement in these patients are poorly understood. Optimal approaches to therapy for this rare disorder have not been

I would like to thank Editage (www.editage.com) for English language editing.

**7. Conclusion**

**Acknowledgements**

**Conflict of interest**

**16**

**Author details**

Vadim Gorodetskiy

Rheumatology, Moscow, Russia

provided the original work is properly cited.

Department of Intensive Methods of Therapy, V.A. Nasonova Research Institute of

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: gorodetskiyblood@mail.ru

[1] Felty AR. Chronic arthritis in the adult associated with splenomegaly and leukopenia. Bull Johns Hopkins Hosp. 1924; 35:16-20

[2] Hanrahan EM, Miller SR. Effect of splenectomy in Felty's syndrome. JAMA. 1932; 99:1247-1252

[3] Balint GP, Balint PV. Felty's syndrome. Best Pract Res Clin Rheumatol. 2004;18,631-645. DOI:10.1016/j.berh.2004.05.002

[4] Spivak JL. Felty's syndrome: an analytical review. Johns Hopkins Med J. 1977;141:156-162

[5] Campion G, Maddison PJ, Goulding N, James I, Ahern MJ, Watt I, Sansom D. The Felty syndrome: a casematched study of clinical manifestations and outcome, serologic features, and immunogenetic associations. Medicine (Baltimore). 1990;69:69-80

[6] Sibley JT, Haga M, Visram DA, Mitchell DM. The clinical course of Felty's syndrome compared to matched controls. J. Rheumatol. 1991;18:1163-1167

[7] Bartels CM, Bell CL, Shinki K, Rosenthal A, Bridges AJ. Changing trends in serious extra-articular manifestations of rheumatoid arthritis among United State veterans over 20 years. Rheumatology (Oxford). 2010;49:1670-1675. DOI: 10.1093/ rheumatology/keq135

[8] Burks EJ, Loughran TP Jr. Pathogenesis of neutropenia in large granular lymphocyte leukemia and Felty syndrome. Blood Rev. 2006;20:245-266. DOI: 10.1016/j.blre.2006.01.003

[9] Turesson C, Schaid DJ, Weyand CM, Jacobsson LT, Goronzy JJ, Petersson IF, Sturfelt G, Nyhäll-Wåhlin BM, Truedsson L, Dechant SA, Matteson EL.

The impact of HLA-DRB1 genes on extra-articular disease manifestations in rheumatoid arthritis. Arthritis Res Ther. 2005;7:R1386–R1393. DOI: 10.1186/ar1837

[10] Rashba EJ, Rowe JM, Packman CH. Treatment of the neutropenia of Felty syndrome. Blood Rev. 1996;10:177-184. DOI: 10.1016/s0268-960x(96) 90024-7

[11] Dwivedi N, Upadhyay J, Neeli I, Khan S, Pattanaik D, Myers L, Kirou KA, Hellmich B, Knuckley B, Thompson PR, Crow MK, Mikuls TR, Csernok E, Radic M. Felty's syndrome autoantibodies bind to deiminated histones and neutrophil extracellular chromatin traps. Arthritis Rheum. 2012;64:982-992. DOI: 10.1002/ art.33432

[12] van Gaalen FA, Toes RE, Ditzel HJ, Schaller M, Breedveld FC, Verweij CL, Huizinga TW. Association of autoantibodies to glucose-6 phosphate isomerase with extraarticular complications in rheumatoid arthritis. Arthritis Rheum. 2004;50:395-399. DOI: 10.1002/art.20028

[13] Ditzel HJ, Masaki Y, Nielsen H, Farnaes L, Burton DR. Cloning and expression of a novel human antibodyantigen pair associated with Felty's syndrome. Proc Natl Acad Sci U S A. 2000;97:9234-9239. DOI: 10.1073/ pnas.97.16.9234

[14] Goldberg J, Pinals RS. Felty syndrome. Semin Arthritis Rheum. 1980;10:52-65. DOI: 10.1016/0049-0172(80)90014-1

[15] Hellmich B, Csernok E, Schatz H, Gross WL, Schnabel A. Autoantibodies against granulocyte colonystimulating factor in Felty's syndrome and neutropenic systemic lupus erythematosus. Arthritis Rheum.

2002;46:2384-2391. DOI: 10.1002/ art.10497

[16] O'Malley DP, George TI, Orazi A, Abbondanzo SL. Benign and Reactive Conditions of Lymph Node and Spleen (Atlas of Nontumor Pathology). 1st ed. American Registry of Pathology Washington, DC in collaboration with the Armed Forces Institute of Pathology Washington, DC; 2009. p.390-391.

[17] Ruderman M, Miller LM, Pinals RS. Clinical and serologic observations on 27 patients with Felty's syndrome. Arthritis Rheum. 1968;11:377-384. DOI: 10.1002/art.1780110302

[18] Barnes CG, Turnbull AL, Vernon-Roberts B. Felty's syndrome. A clinical and pathological survey of 21 patients and their response to treatment. Ann Rheum Dis. 1971;30:359-374. DOI: 10.1136/ard.30.4.359

[19] Sienknecht CW, Urowitz MB, Pruzanski W, Stein HB. Felty's syndrome. Clinical and serological analysis of 34 cases. Ann Rheum Dis. 1977;36:500-507. DOI: 10.1136/ ard.36.6.500

[20] Rosenstein ED, Kramer N. Felty's and pseudo-Felty's syndromes. Semin Arthritis Rheum. 1991;2:129-142. DOI: 10.1016/0049-0172(91)90002-h

[21] Bradley JD, Pinals RS. Felty's syndrome presenting without arthritis. Clin Exp Rheumatol. 1983;1:257-259

[22] Rozin A, Hoffman R, Hayek T, Balbir-Gurman A. Felty's syndrome without rheumatoid arthritis? Clin Rheumatol. 2013;32:701-704. DOI: 10.1007/s10067-012-2157-3

[23] Jain T, Mittal C, Sengupta R, Rubin B. Non-articular Felty's syndrome: An uncommon diagnosis. Neth J Med. 2015;73:435-436

[24] Aslam F, Cheema RS, Feinstein M, Chang-Miller A. Neutropaenia and

splenomegaly without arthritis: think rheumatoid arthritis. BMJ Case Rep. 2018;2018:bcr2018225359. DOI: 10.1136/ bcr-2018-225359

[25] Turesson C, Jacobsson LT, Sturfelt G, Matteson EL, Mathsson L, Rönnelid J. Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis. Ann Rheum Dis. 2007;66:59-64. DOI: 10.1136/ ard.2006.054445

[26] Gorodetskiy VR, Sidorova YV, Kupryshina NA, Vasilyev VI, Probatova NA, Ryzhikova NV, Sudarikov AB. Analysis of a singleinstitution cohort of patients with Felty's syndrome and T-cell large granular lymphocytic leukemia in the setting of rheumatoid arthritis. Rheumatol Int. 2021;41:147-156. doi: 10.1007/s00296-020-04757-4

[27] van Krieken JH, Breedveld FC, te Velde J. The spleen in Felty's syndrome: a histological, morphometrical, and immunohistochemical study. Eur J Haematol. 1988;40:58-64. DOI: 10.1111/ j.1600-0609.1988.tb00797.x

[28] Lazaro E, Morel J. Management of neutropenia in patients with rheumatoid arthritis. Joint Bone Spine. 2015;82:235-239. DOI: 10.1016/j. jbspin.2015.01.005

[29] Stock H, Kadry Z, Smith JP. Surgical management of portal hypertension in Felty's syndrome: A case report and literature review. J Hepatol. 2009;50:831-835. DOI: 10.1016/j. jhep.2008.10.035

[30] Pick AM, Nystrom KK. Nonchemotherapy Drug-Induced Neutropenia and Agranulocytosis: Could Medications be the Culprit? Journal of Pharmacy Practice. 2014;27:447-452. DOI:10.1177/0897190014546115

**19**

clim.2009.03.515

*Felty's Syndrome*

1993;82:1-14

*DOI: http://dx.doi.org/10.5772/intechopen.97080*

[38] Posnett DN, Sinha R, Kabak S, Russo C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med. 1994;179:609-

618. DOI: 10.1084/jem.179.2.609

[39] Delfau-Larue MH, Laroche L, Wechsler J, Lepage E, Lahet C, Asso-Bonnet M, Bagot M, Farcet JP. Diagnostic value of dominant T-cell clones in peripheral blood in 363 patients presenting consecutively with a clinical suspicion of cutaneous lymphoma. Blood. 2000;96:2987-2992

[40] Dippel E, Klemke D, Hummel M, Stein H, Goerdt S. T-cell clonality of undetermined significance. Blood. 2001;98:247-248. DOI: 10.1182/blood.

Arlettaz L, Villard J, Colonna M, Ticheli A, Gratwohl A, Samii K, Chapuis B, Rufer N, Roosnek E. Monoclonal T-cell expansions

[41] Bigouret V, Hoffmann T,

in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors. Blood. 2003;101:3198-3204. DOI: 10.1182/blood-2002-08-2408

[42] Shi M, Olteanu H, Jevremovic D, He R, Viswanatha D, Corley H, Horna P. T-cell clones of uncertain significance are highly prevalent and show close resemblance to T-cell large granular lymphocytic leukemia. Implications for laboratory diagnostics. Mod Pathol. 2020;33:2046-2057. DOI: 10.1038/

[43] Sidorova YV, Sychevskaya KA, Chernova NG, Julhakyan HL, Smirnova SJ,

Conditions May Reduce the Significance of T-cell Clonality Assay for Differential

Ryzhikova NV, Gorodetskiy VR, Naumova EV, Sudarikov AB. High Incidence of Clonal CD8+ T-cell Proliferation in Non-malignant

Diagnosis in Oncohematology.

s41379-020-0568-2

v98.1.247

[31] Salmon JH, Cacoub P, Combe B, Sibilia J, Pallot-Prades B, Fain O, Cantagrel A, Dougados M, Andres E, Meyer O, Carli P, Pertuiset E, Pane I, Maurier F, Ravaud P, Mariette X, Gottenberg JE. Late-onset neutropenia

after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the AutoImmunity and Rituximab registry. RMD Open. 2015;1:e000034. DOI: 10.1136/rmdopen-2014-000034

[32] Loughran TP Jr. Clonal diseases of large granular lymphocytes. Blood.

[33] Bareau B, Rey J, Hamidou M, Donadieu J, Morcet J, Reman O, Schleinitz N, Tournilhac O,

Roussel M, Fest T, Lamy T. Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases. Haematologica. 2010;95:1534-1541. DOI: 10.3324/

haematol.2009.018481

[34] Semenzato G, Zambello R,

DOI: 10.1200/EDBK\_200689

[36] Cheon H, Dziewulska KH, Moosic KB, Olson KC, Gru AA, Feith DJ, Loughran TP Jr. Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Curr Hematol Malig Rep.2020; 15:103-112. DOI: 10.1007/s11899-020-00565-6

[37] Shah A, Diehl LF, St Clair EW. T cell large granular lymphocyte leukemia associated with rheumatoid arthritis and neutropenia. Clin Immunol. 2009;132:145-152. DOI: 10.1016/j.

Starkebaum G, Oshimi K, Loughran TP Jr. The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis. Blood. 1997;89:256-260

[35] Moignet A, Lamy T. Latest advances in the diagnosis and treatment of large granular lymphocytic leukemia. Am Soc Clin Oncol Educ Book. 2018;38:616-625.

#### *Felty's Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97080*

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

splenomegaly without arthritis: think rheumatoid arthritis. BMJ Case Rep. 2018;2018:bcr2018225359. DOI: 10.1136/

Sturfelt G, Matteson EL, Mathsson L, Rönnelid J. Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis. Ann Rheum Dis. 2007;66:59-64. DOI: 10.1136/

[26] Gorodetskiy VR, Sidorova YV, Kupryshina NA, Vasilyev VI, Probatova NA, Ryzhikova NV, Sudarikov AB. Analysis of a singleinstitution cohort of patients with Felty's syndrome and T-cell large granular lymphocytic leukemia in the setting of rheumatoid arthritis. Rheumatol Int. 2021;41:147-156. doi:

10.1007/s00296-020-04757-4

j.1600-0609.1988.tb00797.x

jbspin.2015.01.005

jhep.2008.10.035

[30] Pick AM, Nystrom KK. Nonchemotherapy Drug-Induced Neutropenia and Agranulocytosis:

Could Medications be the Culprit? Journal of Pharmacy Practice. 2014;27:447-452. DOI:10.1177/0897190014546115

[27] van Krieken JH, Breedveld FC, te Velde J. The spleen in Felty's syndrome: a histological, morphometrical, and immunohistochemical study. Eur J Haematol. 1988;40:58-64. DOI: 10.1111/

[28] Lazaro E, Morel J. Management of neutropenia in patients with rheumatoid arthritis. Joint Bone Spine. 2015;82:235-239. DOI: 10.1016/j.

[29] Stock H, Kadry Z, Smith JP. Surgical management of portal hypertension in Felty's syndrome: A case report and literature review. J Hepatol. 2009;50:831-835. DOI: 10.1016/j.

[25] Turesson C, Jacobsson LT,

bcr-2018-225359

ard.2006.054445

2002;46:2384-2391. DOI: 10.1002/

[16] O'Malley DP, George TI, Orazi A, Abbondanzo SL. Benign and Reactive Conditions of Lymph Node and Spleen (Atlas of Nontumor Pathology). 1st ed. American Registry of Pathology Washington, DC in collaboration with the Armed Forces Institute of Pathology Washington, DC; 2009. p.390-391.

[17] Ruderman M, Miller LM, Pinals RS. Clinical and serologic observations on 27 patients with Felty's syndrome. Arthritis Rheum. 1968;11:377-384. DOI:

[18] Barnes CG, Turnbull AL, Vernon-Roberts B. Felty's syndrome. A clinical and pathological survey of 21 patients and their response to treatment. Ann Rheum Dis. 1971;30:359-374. DOI:

[19] Sienknecht CW, Urowitz MB, Pruzanski W, Stein HB. Felty's syndrome. Clinical and serological analysis of 34 cases. Ann Rheum Dis. 1977;36:500-507. DOI: 10.1136/

[20] Rosenstein ED, Kramer N. Felty's and pseudo-Felty's syndromes. Semin Arthritis Rheum. 1991;2:129-142. DOI: 10.1016/0049-0172(91)90002-h

[21] Bradley JD, Pinals RS. Felty's syndrome presenting without arthritis. Clin Exp Rheumatol. 1983;1:257-259

[22] Rozin A, Hoffman R, Hayek T, Balbir-Gurman A. Felty's syndrome without rheumatoid arthritis? Clin Rheumatol. 2013;32:701-704. DOI:

10.1007/s10067-012-2157-3

Neth J Med. 2015;73:435-436

[23] Jain T, Mittal C, Sengupta R, Rubin B. Non-articular Felty's syndrome: An uncommon diagnosis.

[24] Aslam F, Cheema RS, Feinstein M, Chang-Miller A. Neutropaenia and

10.1002/art.1780110302

10.1136/ard.30.4.359

ard.36.6.500

art.10497

**18**

[31] Salmon JH, Cacoub P, Combe B, Sibilia J, Pallot-Prades B, Fain O, Cantagrel A, Dougados M, Andres E, Meyer O, Carli P, Pertuiset E, Pane I, Maurier F, Ravaud P, Mariette X, Gottenberg JE. Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the AutoImmunity and Rituximab registry. RMD Open. 2015;1:e000034. DOI: 10.1136/rmdopen-2014-000034

[32] Loughran TP Jr. Clonal diseases of large granular lymphocytes. Blood. 1993;82:1-14

[33] Bareau B, Rey J, Hamidou M, Donadieu J, Morcet J, Reman O, Schleinitz N, Tournilhac O, Roussel M, Fest T, Lamy T. Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 cases. Haematologica. 2010;95:1534-1541. DOI: 10.3324/ haematol.2009.018481

[34] Semenzato G, Zambello R, Starkebaum G, Oshimi K, Loughran TP Jr. The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis. Blood. 1997;89:256-260

[35] Moignet A, Lamy T. Latest advances in the diagnosis and treatment of large granular lymphocytic leukemia. Am Soc Clin Oncol Educ Book. 2018;38:616-625. DOI: 10.1200/EDBK\_200689

[36] Cheon H, Dziewulska KH, Moosic KB, Olson KC, Gru AA, Feith DJ, Loughran TP Jr. Advances in the Diagnosis and Treatment of Large Granular Lymphocytic Leukemia. Curr Hematol Malig Rep.2020; 15:103-112. DOI: 10.1007/s11899-020-00565-6

[37] Shah A, Diehl LF, St Clair EW. T cell large granular lymphocyte leukemia associated with rheumatoid arthritis and neutropenia. Clin Immunol. 2009;132:145-152. DOI: 10.1016/j. clim.2009.03.515

[38] Posnett DN, Sinha R, Kabak S, Russo C. Clonal populations of T cells in normal elderly humans: the T cell equivalent to "benign monoclonal gammapathy". J Exp Med. 1994;179:609- 618. DOI: 10.1084/jem.179.2.609

[39] Delfau-Larue MH, Laroche L, Wechsler J, Lepage E, Lahet C, Asso-Bonnet M, Bagot M, Farcet JP. Diagnostic value of dominant T-cell clones in peripheral blood in 363 patients presenting consecutively with a clinical suspicion of cutaneous lymphoma. Blood. 2000;96:2987-2992

[40] Dippel E, Klemke D, Hummel M, Stein H, Goerdt S. T-cell clonality of undetermined significance. Blood. 2001;98:247-248. DOI: 10.1182/blood. v98.1.247

[41] Bigouret V, Hoffmann T, Arlettaz L, Villard J, Colonna M, Ticheli A, Gratwohl A, Samii K, Chapuis B, Rufer N, Roosnek E. Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors. Blood. 2003;101:3198-3204. DOI: 10.1182/blood-2002-08-2408

[42] Shi M, Olteanu H, Jevremovic D, He R, Viswanatha D, Corley H, Horna P. T-cell clones of uncertain significance are highly prevalent and show close resemblance to T-cell large granular lymphocytic leukemia. Implications for laboratory diagnostics. Mod Pathol. 2020;33:2046-2057. DOI: 10.1038/ s41379-020-0568-2

[43] Sidorova YV, Sychevskaya KA, Chernova NG, Julhakyan HL, Smirnova SJ, Ryzhikova NV, Gorodetskiy VR, Naumova EV, Sudarikov AB. High Incidence of Clonal CD8+ T-cell Proliferation in Non-malignant Conditions May Reduce the Significance of T-cell Clonality Assay for Differential Diagnosis in Oncohematology.

Clin Lymphoma Myeloma Leuk. 2020;20:203-208. DOI: 10.1016/j. clml.2019.12.021

[44] Thorne C, Urowitz MB. Long-term outcome in Felty's syndrome. Ann Rheum Dis. 1982;41:486-489. DOI: 10.1136/ard.41.5.486

[45] Narváez J, Domingo-Domenech E, Gómez-Vaquero C, López-Vives L, Estrada P, Aparicio M, Martín-Esteve I, Nolla JM. Biological agents in the management of Felty's syndrome: a systematic review. Semin Arthritis Rheum. 2012;41:658-668. DOI: 10.1016/j.semarthrit.2011.08.008

[46] Wang CR, Chiu YC, Chen YC. Successful treatment of refractory neutropenia in Felty's syndrome with rituximab. Scand J Rheumatol. 2018;47:340-341. DOI: 10.1080/03009742.2017.1334816

[47] Yazıcı A, Uçar A, Mehtap Ö, Gönüllü EÖ, Tamer A. Presentation of three cases followed up with a diagnosis of Felty syndrome. Eur J Rheumatol. 2014;1:120-122. DOI: 10.5152/ eurjrheumatol.2014.026

**21**

**Chapter 3**

**Abstract**

for patients.

Erythema nodosum

**1. Introduction**

and hilar adenopathy.

**2. Epidemiology**

Löfgren's Syndrome

*Shiyu Wang and Shailendra Singh*

Löfgren's syndrome presents as acute sarcoid arthritis, with a triad of hilar adenopathy, acute polyarthritis and erythema nodosum. Löfgren's syndrome is self-limited, erythema nodosum, hilar adenopathy and acute polyarthritis usually resolve within a few weeks to months, however polyarthritis can last for up to 2 years. Treatment involves symptomatic control with NSAIDs/colchicine or oral glucocorticoids until symptoms resolve, if disease is resistant to these therapies, hydroxychloroquine, methotrexate or infliximab can be used. Löfgren's syndrome is a rare presentation of sarcoidosis occurring in only about 5–10% of sarcoid patients. It is, however, important to recognize as it is the most common form of acute sarcoid arthritis and prompt treatment can prevent unnecessary prolonged discomfort

**Keywords:** Löfgren's Syndrome, Sarcoidosis, Polyarthritis, Hilar adenopathy,

Löfgren's syndrome is an acute manifestation of sarcoidosis. Sarcoidosis is a disease characterized by noncaseating granulomas throughout multiple body systems, most commonly involving the lungs (> 90% cases), often manifesting as hilar adenopathy. A small subset of patients (~10%) will develop joints symptoms, which can manifest as either acute or chronic arthritis. Löfgren's syndrome is the most common presentation of acute sarcoid arthritis, occurring in about 5–10% of sarcoid cases, presenting as classical triad of acute polyarthritis, erythema nodosum

Sarcoidosis is a disease with prevalence of about 10 to 20 per 100,000 people, it affects a wide variety of patients, but there are certain predilections and patterns for higher disease activity. Geographic area, ethnicity, gender and age seem to play important roles in incidence and presentation of disease [1, 2]. Various geographic locations have been studied, and there seems to be clustering of sarcoidosis incidence around certain geographic areas, with northern countries (such as Scandinavia) having much higher incidence than other areas [3]. Ethnicity also has a distinct pattern, with African Americans, Scandinavians, Afro Caribbeans, Irish, Puerto Rican and North Africans having highest incidence, though this seems to be affected by geographical location as well [3, 4]. There are also differences in disease presentation between different ethnicities; African Americans seem to have more

## **Chapter 3** Löfgren's Syndrome

*Shiyu Wang and Shailendra Singh*

### **Abstract**

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

[44] Thorne C, Urowitz MB. Long-term outcome in Felty's syndrome. Ann Rheum Dis. 1982;41:486-489. DOI:

[45] Narváez J, Domingo-Domenech E, Gómez-Vaquero C, López-Vives L, Estrada P, Aparicio M, Martín-Esteve I, Nolla JM. Biological agents in the management of Felty's syndrome: a systematic review. Semin Arthritis Rheum. 2012;41:658-668. DOI: 10.1016/j.semarthrit.2011.08.008

[46] Wang CR, Chiu YC, Chen YC. Successful treatment of refractory neutropenia in Felty's syndrome

Rheumatol. 2018;47:340-341. DOI: 10.1080/03009742.2017.1334816

[47] Yazıcı A, Uçar A, Mehtap Ö, Gönüllü EÖ, Tamer A. Presentation of three cases followed up with a diagnosis of Felty syndrome. Eur J Rheumatol. 2014;1:120-122. DOI: 10.5152/ eurjrheumatol.2014.026

with rituximab. Scand J

Clin Lymphoma Myeloma Leuk. 2020;20:203-208. DOI: 10.1016/j.

clml.2019.12.021

10.1136/ard.41.5.486

**20**

Löfgren's syndrome presents as acute sarcoid arthritis, with a triad of hilar adenopathy, acute polyarthritis and erythema nodosum. Löfgren's syndrome is self-limited, erythema nodosum, hilar adenopathy and acute polyarthritis usually resolve within a few weeks to months, however polyarthritis can last for up to 2 years. Treatment involves symptomatic control with NSAIDs/colchicine or oral glucocorticoids until symptoms resolve, if disease is resistant to these therapies, hydroxychloroquine, methotrexate or infliximab can be used. Löfgren's syndrome is a rare presentation of sarcoidosis occurring in only about 5–10% of sarcoid patients. It is, however, important to recognize as it is the most common form of acute sarcoid arthritis and prompt treatment can prevent unnecessary prolonged discomfort for patients.

**Keywords:** Löfgren's Syndrome, Sarcoidosis, Polyarthritis, Hilar adenopathy, Erythema nodosum

#### **1. Introduction**

Löfgren's syndrome is an acute manifestation of sarcoidosis. Sarcoidosis is a disease characterized by noncaseating granulomas throughout multiple body systems, most commonly involving the lungs (> 90% cases), often manifesting as hilar adenopathy. A small subset of patients (~10%) will develop joints symptoms, which can manifest as either acute or chronic arthritis. Löfgren's syndrome is the most common presentation of acute sarcoid arthritis, occurring in about 5–10% of sarcoid cases, presenting as classical triad of acute polyarthritis, erythema nodosum and hilar adenopathy.

#### **2. Epidemiology**

Sarcoidosis is a disease with prevalence of about 10 to 20 per 100,000 people, it affects a wide variety of patients, but there are certain predilections and patterns for higher disease activity. Geographic area, ethnicity, gender and age seem to play important roles in incidence and presentation of disease [1, 2]. Various geographic locations have been studied, and there seems to be clustering of sarcoidosis incidence around certain geographic areas, with northern countries (such as Scandinavia) having much higher incidence than other areas [3]. Ethnicity also has a distinct pattern, with African Americans, Scandinavians, Afro Caribbeans, Irish, Puerto Rican and North Africans having highest incidence, though this seems to be affected by geographical location as well [3, 4]. There are also differences in disease presentation between different ethnicities; African Americans seem to have more

severe disease presentation than Caucasians [2]. Lowest incidence occurs in Spain and Japan [3, 4]. Women are overall more affected by sarcoidosis than men, though interestingly, the age of diagnosis is almost 10 years later in women than men in many populations [3, 4]. There also seem to be difference in disease presentation between women and men, with women potentially experiencing more musculoskeletal related symptoms [3]. Sarcoidosis incidence also increases with family history of the disease; studies have shown that alleles on short arm of chromosome 6 seem to confer increased risk (HLA DR 11, 12, 14, 15, 17) or protection (HLA DRI, DR4) from disease [5].

Löfgren's syndrome follows many of the same epidemiologic trends of sarcoidosis. It affects women more than men, with Scandinavian ethnicity having the highest incidence [6, 7]. There also seems to be a temporal clustering of incidence, with rates highest in the months from March to July [6]. The age of onset was, however; significantly lower for Löfgren's syndrome than sarcodosis, at 39 years old versus 47 years old [7]. There also are differences between sexes in regards to presentation, women are more likely to present with erythema nodosum, whereas men are more likely to have inflammation or arthritis of ankles without erythema nodosum [8]. Various genetic factors and alleles have been associated with Löfgren's syndrome, some protective and leading to better outcomes (HLA DQB1\*0201, DRB1\*03) while others are associated with more severe disease and worse outcomes (CCR2, HLA DQ2, DR3) [6, 9–12].

#### **3. Etiology**

The etiology of sarcoidosis, and by extension Löfgren's syndrome, is poorly understood. Granulomatous inflammation leads to eventual noncaseating granulomas in various organs. Formation of granulomas is due to exaggerated cell mediated immune response to antigens. The exact antigen(s) that stimulate sarcoidosis is unclear at this point in time. Many studies analyzing a large number of patients have not found one factor(s) that clearly causes sarcoidosis [13], possibly due to there being many different underlying causes of sacroidosis that leads to similar presentations. Some of the possible etiologies explored to date are environmental exposures and infectious agents.

#### **3.1 Environmental exposure**

Certain chemical elements (Beryllium, Zirconium, Aluminum) have been shown to cause graulomatous disease in lungs of patients with occupational exposure to these elements, while they themselves do not cause sarcoidosis, various studies have investigated if other environmental exposures could [14–16]. Specifically, rescue workers exposed to World Trade Center dust and debris developed new onset sarcoidosis, possible due to exposure to a yet unknown component of the dust [17].

#### **3.2 Infectious agent**

Mycobacterium and Propionibacteria have been studied as possible causes of sarcoidosis [18, 19]. *Mycobacterium tuberculosis* causes granulmatous caseations similar to those seen in sarcoidosis, and there have been *Mycobacterium tuberculosis* components found in sacroidosis tissue [20]. Propionibacteria acnes have also been found in lymph nodes of sarcoidosis patients [19]. Despite these findings, there has been no casual relationship found between these infectious agents and sacroidosis. Further evidence to support an infectious etiology of sarcoidosis is that transplantations of various organs have been shown to induce sarcoidosis in recipient [21–23].

**23**

**Figure 1.**

*org/licenses/by-sa/3.0/>, via Wikimedia Commons).*

*Löfgren's Syndrome*

**4. Pathophysiology**

to form granulomas.

*DOI: http://dx.doi.org/10.5772/intechopen.97154*

ing extrapulmonary symptoms (**Figure 1**) [26].

**4.1 Erythema Nodosum and acute polyarthritis**

The pathophysiology of sarcoidosis, and by extension Löfgren's syndrome, involves activation of immune cells by as of yet unknown antigen(s). While the end

This process seems to occur most prominent and commonly in the lungs, with alveolar macrophages often the first to aggregate to form granulomas. This process can occur in other areas of the body, as evidence by up to 30% of patient experienc-

In Löfgren's syndrome, in addition to pulmonary granolumas (represented as hilar adenopathy), there are also manifestations of erythema nodosum and acute polyarthritis. Erythema nodosum is caused by delayed type hypersensitivity reaction from exposure to antigens. Its exact pathophysiology is not fully understood, but may be due to immune complex deposition in venules of subcutaneous

*Non-caseating granuloma (Samir at the English-language Wikipedia, CC BY-SA 3.0 <http://creativecommons.*

result is graumloma formation, there are quite a few steps before this stage. Antigen presenting cells (APCs), either macrophages or dendritic cells, phagocytose the as of yet unknown antigen(s), and then presents this antigen(s) to Helper CD4+ T cells. These Helper T cells then expresses various inflammatory cytokines including: interferon-gamma, Tumor necrosis factor (TNF), interleukin (IL)-2, IL-17 and IL-22 [24]. IL-17 recruits T Helper 17 (Th17) cells which then produce even more inflammatory cytokines, primarily interferongamma [25]. All these inflammatory mediators cause fusion of APCs into multinucleated giant cells, the APCs and multinucleated giant cells then cluster

### **4. Pathophysiology**

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

from disease [5].

**3. Etiology**

exposures and infectious agents.

**3.1 Environmental exposure**

**3.2 Infectious agent**

severe disease presentation than Caucasians [2]. Lowest incidence occurs in Spain and Japan [3, 4]. Women are overall more affected by sarcoidosis than men, though interestingly, the age of diagnosis is almost 10 years later in women than men in many populations [3, 4]. There also seem to be difference in disease presentation between women and men, with women potentially experiencing more musculoskeletal related symptoms [3]. Sarcoidosis incidence also increases with family history of the disease; studies have shown that alleles on short arm of chromosome 6 seem to confer increased risk (HLA DR 11, 12, 14, 15, 17) or protection (HLA DRI, DR4)

Löfgren's syndrome follows many of the same epidemiologic trends of sarcoidosis.

It affects women more than men, with Scandinavian ethnicity having the highest incidence [6, 7]. There also seems to be a temporal clustering of incidence, with rates highest in the months from March to July [6]. The age of onset was, however; significantly lower for Löfgren's syndrome than sarcodosis, at 39 years old versus 47 years old [7]. There also are differences between sexes in regards to presentation, women are more likely to present with erythema nodosum, whereas men are more likely to have inflammation or arthritis of ankles without erythema nodosum [8]. Various genetic factors and alleles have been associated with Löfgren's syndrome, some protective and leading to better outcomes (HLA DQB1\*0201, DRB1\*03) while others are associated with more severe disease and worse outcomes (CCR2, HLA DQ2, DR3) [6, 9–12].

The etiology of sarcoidosis, and by extension Löfgren's syndrome, is poorly understood. Granulomatous inflammation leads to eventual noncaseating granulomas in various organs. Formation of granulomas is due to exaggerated cell mediated immune response to antigens. The exact antigen(s) that stimulate sarcoidosis is unclear at this point in time. Many studies analyzing a large number of patients have not found one factor(s) that clearly causes sarcoidosis [13], possibly due to there being many different underlying causes of sacroidosis that leads to similar presentations. Some of the possible etiologies explored to date are environmental

Certain chemical elements (Beryllium, Zirconium, Aluminum) have been shown to cause graulomatous disease in lungs of patients with occupational exposure to these elements, while they themselves do not cause sarcoidosis, various studies have investigated if other environmental exposures could [14–16]. Specifically, rescue workers exposed to World Trade Center dust and debris developed new onset sarcoidosis, possible due to exposure to a yet unknown component of the dust [17].

Mycobacterium and Propionibacteria have been studied as possible causes of sarcoidosis [18, 19]. *Mycobacterium tuberculosis* causes granulmatous caseations similar to those seen in sarcoidosis, and there have been *Mycobacterium tuberculosis* components found in sacroidosis tissue [20]. Propionibacteria acnes have also been found in lymph nodes of sarcoidosis patients [19]. Despite these findings, there has been no casual relationship found between these infectious agents and sacroidosis. Further evidence to support an infectious etiology of sarcoidosis is that transplantations of various organs have been shown to induce sarcoidosis in recipient [21–23].

**22**

The pathophysiology of sarcoidosis, and by extension Löfgren's syndrome, involves activation of immune cells by as of yet unknown antigen(s). While the end result is graumloma formation, there are quite a few steps before this stage.

Antigen presenting cells (APCs), either macrophages or dendritic cells, phagocytose the as of yet unknown antigen(s), and then presents this antigen(s) to Helper CD4+ T cells. These Helper T cells then expresses various inflammatory cytokines including: interferon-gamma, Tumor necrosis factor (TNF), interleukin (IL)-2, IL-17 and IL-22 [24]. IL-17 recruits T Helper 17 (Th17) cells which then produce even more inflammatory cytokines, primarily interferongamma [25]. All these inflammatory mediators cause fusion of APCs into multinucleated giant cells, the APCs and multinucleated giant cells then cluster to form granulomas.

This process seems to occur most prominent and commonly in the lungs, with alveolar macrophages often the first to aggregate to form granulomas. This process can occur in other areas of the body, as evidence by up to 30% of patient experiencing extrapulmonary symptoms (**Figure 1**) [26].

#### **4.1 Erythema Nodosum and acute polyarthritis**

In Löfgren's syndrome, in addition to pulmonary granolumas (represented as hilar adenopathy), there are also manifestations of erythema nodosum and acute polyarthritis. Erythema nodosum is caused by delayed type hypersensitivity reaction from exposure to antigens. Its exact pathophysiology is not fully understood, but may be due to immune complex deposition in venules of subcutaneous

#### **Figure 1.**

*Non-caseating granuloma (Samir at the English-language Wikipedia, CC BY-SA 3.0 <http://creativecommons. org/licenses/by-sa/3.0/>, via Wikimedia Commons).*

fat, inciting an inflammatory reaction and granuloma formation [27]. Acute polyarthritis also has poorly understood pathogenesis, but may be due increased inflammatory milieu within the body, leading to transient inflammatory arthritis.

#### **5. Presentation**

Löfgren's syndrome presents classically as a triad of hilar lympadenopathy, erythema nodosum and acute polyarthritis. Often constitutional symptoms occur concurrently with the above triad, most commonly manifesting as fever, fatigue and malaise. Age of onset is generally under or around 40 years of age. More rare symptoms include uveitis along with blurry vision and light sensitivity [28]. There is variability in presentation between different sexes [8].

#### **5.1 Hilar lymphadenopathy**

Hilar lyphadenopathy is a classic finding of pulmonary sarcoidosis, making it ubiquitous in Löfgren's syndrome. It is a radiographic term for enlarged mediastinal lymph nodes, most often those surrounding the pulmonary hila or root of the lung, where the lungs connect to the trachea and heart. Often the enlargement is bilateral and symmetric, though the right side may be slightly more prominent. Chest radiograph is required for definitive diagnosis, and there are five stages, as discussed below. These stages do not represent disease activity, just anatomical findings on chest radiography [29]. Generally, hilar lympadenopathy will regress within 1 year [30]. Though not exclusively caused by bilateral hilar lympadenopathy, respiratory symptoms are often the first presentation that prompts obtaining a chest radiograph, where hilar lymphadenopathy is first discovered in a patient. These respiratory symptoms most commonly are coughing, dyspnea and chest pain (**Table 1** and **Figures 2** and **3**).

#### **5.2 Erythema Nodosum**

Erythema nodosum presents as erythematous, tender, immobile nodules that are elevated and can join to form a plaque. Most commonly, they present on shins in Löfgren's syndrome, though they can also appear on head and neck regions as well. These nodules are caused by subcutaneous inflammation, and are frequently accompanied by fevers and take a few days to develop. Spontaneous resolution typically occurs within eight weeks without scarring. There may be hyperpigmentation after resolution, but this is rare [27]. Relapsing erythema nodosum


**25**

**Figure 3.**

nodosum (**Figure 4**) [8].

**5.3 Acute polyarthritis**

*Löfgren's Syndrome*

**Figure 2.**

*Bruce Dull, MD).*

*DOI: http://dx.doi.org/10.5772/intechopen.97154*

can develop; this represents poor control or failure of treatment of underlying chronic condition. Erythema nodosum is also more commonly seen in women with Löfgren's syndrome, whereas men can have acute polyarthritis with no erythema

*4.0, https://commons.wikimedia.org/w/index.php?curid=49068286).*

*Computed tomography of bilateral hilar lymphadenopathy (by James Heilman, MD - Own work, CC BY-SA* 

*Anterior–posterior and lateral chest radiograph of bilateral hilar lymphadenopathy (image courtesy of H.* 

Acute polyarthritis in Löfgren's syndrome is typically symmetrical and oligoarticular (affecting 2 to 4 joints) initially. Most often, it involves the ankles bilaterally and then starts to affects other joints of the lower extremities such as knees and

#### **Table 1.** *Stages of pulmonary sarcoidosis.*

**Figure 2.**

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

is variability in presentation between different sexes [8].

**5. Presentation**

**5.1 Hilar lymphadenopathy**

(**Table 1** and **Figures 2** and **3**).

**5.2 Erythema Nodosum**

**Stages of Pulmonary Sarcoidosis**

*Stages of pulmonary sarcoidosis.*

fat, inciting an inflammatory reaction and granuloma formation [27]. Acute polyarthritis also has poorly understood pathogenesis, but may be due increased inflammatory milieu within the body, leading to transient inflammatory arthritis.

Löfgren's syndrome presents classically as a triad of hilar lympadenopathy, erythema nodosum and acute polyarthritis. Often constitutional symptoms occur concurrently with the above triad, most commonly manifesting as fever, fatigue and malaise. Age of onset is generally under or around 40 years of age. More rare symptoms include uveitis along with blurry vision and light sensitivity [28]. There

Hilar lyphadenopathy is a classic finding of pulmonary sarcoidosis, making it ubiquitous in Löfgren's syndrome. It is a radiographic term for enlarged mediastinal lymph nodes, most often those surrounding the pulmonary hila or root of the lung, where the lungs connect to the trachea and heart. Often the enlargement is bilateral and symmetric, though the right side may be slightly more prominent. Chest radiograph is required for definitive diagnosis, and there are five stages, as discussed below. These stages do not represent disease activity, just anatomical findings on chest radiography [29]. Generally, hilar lympadenopathy will regress within 1 year [30]. Though not exclusively caused by bilateral hilar lympadenopathy, respiratory symptoms are often the first presentation that prompts obtaining a chest radiograph, where hilar lymphadenopathy is first discovered in a patient. These respiratory symptoms most commonly are coughing, dyspnea and chest pain

Erythema nodosum presents as erythematous, tender, immobile nodules that are elevated and can join to form a plaque. Most commonly, they present on shins in Löfgren's syndrome, though they can also appear on head and neck regions as well. These nodules are caused by subcutaneous inflammation, and are frequently accompanied by fevers and take a few days to develop. Spontaneous resolution typically occurs within eight weeks without scarring. There may be hyperpigmentation after resolution, but this is rare [27]. Relapsing erythema nodosum

Stage II Bilateral hilar lymphadenopathy + Diffuse infiltrative lung damage

**Features**

Stage 0 Normal chest radiograph Stage I Bilateral hilar lymphadenopathy

Stage IV Lung fibrosis1

Stage III Diffuse infiltrative lung damage

*The Foundations in Diagnostic Pathology Series, Pulmonary Pathology – Chapter 17.*

**24**

*1*

**Table 1.**

*Anterior–posterior and lateral chest radiograph of bilateral hilar lymphadenopathy (image courtesy of H. Bruce Dull, MD).*

#### **Figure 3.**

*Computed tomography of bilateral hilar lymphadenopathy (by James Heilman, MD - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=49068286).*

can develop; this represents poor control or failure of treatment of underlying chronic condition. Erythema nodosum is also more commonly seen in women with Löfgren's syndrome, whereas men can have acute polyarthritis with no erythema nodosum (**Figure 4**) [8].

#### **5.3 Acute polyarthritis**

Acute polyarthritis in Löfgren's syndrome is typically symmetrical and oligoarticular (affecting 2 to 4 joints) initially. Most often, it involves the ankles bilaterally and then starts to affects other joints of the lower extremities such as knees and

#### **Figure 4.**

*Erythema nodosum of lower extremities (by James Heilman, MD - Own work, CC BY-SA 3.0, https:// commons.wikimedia.org/w/index.php?curid=11520780).*

can also affect wrists and elbow joints as well. Bilateral ankle arthritis seems to be the most common initial manifestation of acute polyarthritis. Rarely, small joints of hands bilaterally can be involved [30]. Arthritis generally resolves within a few months, though it can persist up to 2 years, even with treatment. Cases of recurrent arthritis after treatment have also been described [31]. Men present with acute polyarthritis more commonly [8].

#### **6. Evaluation and diagnosis**

There are no definitive test or classification criteria for Löfgren's syndrome, and though the classic triad of hilar lympadenopathy, erythema nodosum and acute polyarthritis are highly specific (> 95%), there are instances where not all components are presents in patients with Löfgren's syndrome [32]. For successful evaluation of a patient with Löfgren's syndrome, an accurate and detail history and physical must first be performed, usually followed up with a chest radiograph to confirm diagnosis. Biopsies may be indicated for definitive diagnosis of sarcoidosis if chest radiograph or other forms of imaging are inconclusive. Laboratory testing is generally not required.

#### **6.1 History and physical exam**

A detailed and accurate history and physical exam is essential for evaluation and diagnosis of Löfgren's syndrome. Chronicity and specificity symptoms need to be elucidated and investigated. Importantly, history should uncover onset and location of acute polyarthritis, and whether there has been any migration of arthritis. Underlying arthritis or arthralgias should also be clarified, to ensure that the acute polyarthritis is indeed new and acute in nature, not a continuation of previous disease. Constitutional symptoms should also be inquired about, as acute onset of fever very often accompanies both the acute polyarthritis and development of erythema nodosum. Ask about respiratory symptoms, as they can be the first sign

**27**

*Löfgren's Syndrome*

erythema nodosum.

**6.2 Chest radiography**

**6.3 Biopsies**

sarcoidosis [34].

**6.4 Laboratory and genetic testing**

erythema nodosum as well as hilar adenopathy.

found to be risk factors for worse outcomes [9–12].

*DOI: http://dx.doi.org/10.5772/intechopen.97154*

of previously unknown hilar lymphadenopathy. Keep in mind the differences in presentation between men and women, as women may not have presentation of acute polyarthritis and just erythema nodosum, whereas men may not present with

Physical exam should include detailed examination of lower extremities, neck and head regions for erythema nodosum. Joint examination of lower extremities as well as hands, wrists and elbows should be performed to see if there is pain, tenderness, swelling, redness and heat. Monitoring temperature can also be useful in determining if there is accompanying fever with these symptoms. A detailed cardiac, pulmonary and abdominal exam should be performed as hilar adenopathy and sarcoidosis in general can cause various manifestations and physical changes in these areas.

Chest radiography should be obtained at least once on all patients suspected with Löfgren's syndrome, it is an essential step to establishing if there his hilar lymphadenopathy. Section 5.1 describes findings and diagnostic criteria for hilar lymphadenopathy on chest radiograph. If chest radiography is inconclusive, high resolution computed tomography (HRCT) scan can be performed, and provides more detailed imaging and analysis of mesiatinum, able to identify in more detail the precise location and extent of lympadenopathy [33]. HRCT is not routinely

Biopsies are generally limited to cases of Löfgren's syndrome where HRCT or other imaging modalities cannot detect sarcoidosis, and/or disease is refractory to treatment or deviates from expected course. It is utilized to definitively obtain tissue samples that confirm diagnosis of sarcoidosis. Generally, bronchoalveolar lavage (BAL) is performed with endobronchial or transbronchial biopsies, endobronchial ultrasound (EBUS) biopsy can also be used for various positions and angles to attempt a needle aspiration biopsy of lympadenopathy. A triad of CD4 to CD8 cell ratio > 4, lymphocyte percentage > 16% and presence of noncaseating granulomas has 100% positive predictive value and 81% negative predictive value for diagnosis of

Laboratory testing is generally not required for evaluation and diagnosis of Löfgren's syndrome. Many laboratory testing is non-specific and do not provide additional value. Exceptions may include angiotensin-converting enzyme (ACE) and ionized calcium. Studies have shown that patients with elevated ACE and ionized calcium may have increased risk for prolonged arthritis [35]. Tuberculosis skin or interferon-gamma testing should be performed at least once on patients suspected with Löfgren's syndrome to rule out tuberculosis, which can mimic

Genetic testing is not required for evaluation and diagnosis of Löfgren's syndrome. Though some alleles and genes have been associated with Löfgren's syndrome, they are more for academic research purposes rather than to diagnose the disease. Associations include: HLA DQB1\*0201 and DRB1\*03 have been found to be protective and lead to better outcomes, and CCR2, HLA DQ2 and DR3 have been

recommended for evaluation and diagnosis of Löfgren's syndrome.

#### *Löfgren's Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97154*

of previously unknown hilar lymphadenopathy. Keep in mind the differences in presentation between men and women, as women may not have presentation of acute polyarthritis and just erythema nodosum, whereas men may not present with erythema nodosum.

Physical exam should include detailed examination of lower extremities, neck and head regions for erythema nodosum. Joint examination of lower extremities as well as hands, wrists and elbows should be performed to see if there is pain, tenderness, swelling, redness and heat. Monitoring temperature can also be useful in determining if there is accompanying fever with these symptoms. A detailed cardiac, pulmonary and abdominal exam should be performed as hilar adenopathy and sarcoidosis in general can cause various manifestations and physical changes in these areas.

#### **6.2 Chest radiography**

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

polyarthritis more commonly [8].

*commons.wikimedia.org/w/index.php?curid=11520780).*

**6. Evaluation and diagnosis**

**6.1 History and physical exam**

can also affect wrists and elbow joints as well. Bilateral ankle arthritis seems to be the most common initial manifestation of acute polyarthritis. Rarely, small joints of hands bilaterally can be involved [30]. Arthritis generally resolves within a few months, though it can persist up to 2 years, even with treatment. Cases of recurrent arthritis after treatment have also been described [31]. Men present with acute

*Erythema nodosum of lower extremities (by James Heilman, MD - Own work, CC BY-SA 3.0, https://*

There are no definitive test or classification criteria for Löfgren's syndrome, and though the classic triad of hilar lympadenopathy, erythema nodosum and acute polyarthritis are highly specific (> 95%), there are instances where not all components are presents in patients with Löfgren's syndrome [32]. For successful evaluation of a patient with Löfgren's syndrome, an accurate and detail history and physical must first be performed, usually followed up with a chest radiograph to confirm diagnosis. Biopsies may be indicated for definitive diagnosis of sarcoidosis if chest radiograph or other forms of imaging are inconclusive. Laboratory testing is generally not

A detailed and accurate history and physical exam is essential for evaluation and diagnosis of Löfgren's syndrome. Chronicity and specificity symptoms need to be elucidated and investigated. Importantly, history should uncover onset and location of acute polyarthritis, and whether there has been any migration of arthritis. Underlying arthritis or arthralgias should also be clarified, to ensure that the acute polyarthritis is indeed new and acute in nature, not a continuation of previous disease. Constitutional symptoms should also be inquired about, as acute onset of fever very often accompanies both the acute polyarthritis and development of erythema nodosum. Ask about respiratory symptoms, as they can be the first sign

**26**

required.

**Figure 4.**

Chest radiography should be obtained at least once on all patients suspected with Löfgren's syndrome, it is an essential step to establishing if there his hilar lymphadenopathy. Section 5.1 describes findings and diagnostic criteria for hilar lymphadenopathy on chest radiograph. If chest radiography is inconclusive, high resolution computed tomography (HRCT) scan can be performed, and provides more detailed imaging and analysis of mesiatinum, able to identify in more detail the precise location and extent of lympadenopathy [33]. HRCT is not routinely recommended for evaluation and diagnosis of Löfgren's syndrome.

#### **6.3 Biopsies**

Biopsies are generally limited to cases of Löfgren's syndrome where HRCT or other imaging modalities cannot detect sarcoidosis, and/or disease is refractory to treatment or deviates from expected course. It is utilized to definitively obtain tissue samples that confirm diagnosis of sarcoidosis. Generally, bronchoalveolar lavage (BAL) is performed with endobronchial or transbronchial biopsies, endobronchial ultrasound (EBUS) biopsy can also be used for various positions and angles to attempt a needle aspiration biopsy of lympadenopathy. A triad of CD4 to CD8 cell ratio > 4, lymphocyte percentage > 16% and presence of noncaseating granulomas has 100% positive predictive value and 81% negative predictive value for diagnosis of sarcoidosis [34].

#### **6.4 Laboratory and genetic testing**

Laboratory testing is generally not required for evaluation and diagnosis of Löfgren's syndrome. Many laboratory testing is non-specific and do not provide additional value. Exceptions may include angiotensin-converting enzyme (ACE) and ionized calcium. Studies have shown that patients with elevated ACE and ionized calcium may have increased risk for prolonged arthritis [35]. Tuberculosis skin or interferon-gamma testing should be performed at least once on patients suspected with Löfgren's syndrome to rule out tuberculosis, which can mimic erythema nodosum as well as hilar adenopathy.

Genetic testing is not required for evaluation and diagnosis of Löfgren's syndrome. Though some alleles and genes have been associated with Löfgren's syndrome, they are more for academic research purposes rather than to diagnose the disease. Associations include: HLA DQB1\*0201 and DRB1\*03 have been found to be protective and lead to better outcomes, and CCR2, HLA DQ2 and DR3 have been found to be risk factors for worse outcomes [9–12].

#### **7. Differential diagnoses**

Many conditions and diseases can cause erythema nodosum, polyarthritis and associated fever. These including: infections, drug reactions, malignancies, inflammatory bowel disease and other rheumatologic conditions. While chest radiograph with findings of hilar adenopathy can significantly increase specificity for Löfgren's syndrome, it is not always necessary and a detailed history and physical should be able to differentiate many of the other differential diagnoses listed below.

#### **7.1 Infections**

A wide variety of infections can cause erythema nodosum and arthritis, which can manifest as reactive arthritis or infectious arthritis. These include bacterial: streptococcous, chalymdia, yersinina, salmonella, campylobacter and tubcerculosis. Fungal: coccidiomycosis, histoplasmosis, blastomycosis. Viral: hepatitis B and infectious mononucleosis. Reactive and infectious arthritis generally present initially in the knee joint, which can overlap with Löfgren's syndrome, and the arthritis are also usually self-limited and acute. Therefore it can be difficult to distinguish between the two without chest radiography, but presence of hilar lymphadenopathy should exclude most of the infections listed above. The exception to this is tuberculosis, which can also present with hilar adenopathy, thus it is necessary to obtain tuberculosis skin or interferon-gamma testing to rule out tuberculosis infection.

#### **7.2 Drug reactions**

Drug reactions that can cause erythema nodosum include: oral contraceptives, penicillins, sulfonamides, bromides, iodides and TNF Alpha inhibitors. Though drug reactions can cause fever, very rarely do they cause arthritis. Cessation of offending drug also often resolves symptoms. Thus, if there is no presence of acute polyarthritis, distinguishing a drug reaction from Löfgren's syndrome is clear.

#### **7.3 Malignancies**

Malignancies that can cause erythema nodosum include lymphoma, leukemia and carcinomas. These malignancies can also be associated with fever, but also very rarely cause arthritis. They can, however, cause hilar lymphadenopathy, thus it is important to delineate presence of acute polyarthritis.

#### **7.4 Inflammatory bowel disease (IBD)**

Ulcerative colitis and Crohns disease can cause erythema nodosum with associated fever as well as enteropathic arthritis. Enteropathic arthritis can present sporadically and intermittently, and can be mistaken for acute polyarthritis. Therefore, it is difficult to distinguish between inflammatory bowel disease and Löfgren's syndrome, chest radiography should be obtained to detect for presence of hilar adenopathy. IBD generally does not cause hilar lymphadenopathy.

#### **7.5 Other rheumatologic conditions**

Rheumatologic conditions such as Behcet disease and Sweet syndrome can also cause erythema nodosum, arthritis with associated fevers. Behcet syndrome causes polyarthritis of lower extremity joints, very similar to Löfgren's syndrome. Sweet

**29**

*Löfgren's Syndrome*

**9. Prognosis**

are exceedingly rare [35].

**10. Conclusions**

**Conflict of interest**

*DOI: http://dx.doi.org/10.5772/intechopen.97154*

them from Löfgren's syndrome.

**8. Treatment/management**

syndrome itself does not cause arthritis, but is associated with rheumatoid arthritis, IBD and Behcet syndrome, all of which can cause arthritis. Sweet syndrome is associated with a characteristic rash that present as erythematous plaques, which should be differentiated from erythema nodosum. Neither condition is associated with hilar lymphadenopathy, thus chest radiography should be obtained to distinguish

Löfgren's syndrome is largely a self-limited disease, the erythema nodosum, acute polyarthritis and hilar lymphadenopathy resolves usually within a few weeks to months, most cases resolve within 1 year. Polyarthritis has been known to last up to 2 years. Treatment is largely supportive and goal is symptomatic control. NSAIDs are first line for anti-inflammatory properties to ameliorate discomfort of fever, erythema nodosum and arthritis; colchcine can also be used for this purpose. In severe or refractory cases, glucocorticoids can be used, which needs to be tapered off of once symptoms have been resolved. Further interventions with methotrexate

Prognosis of Löfgren's syndrome is excellent; most patients achieve complete resolution of symptoms without recurrence in 6 months to 2 years. Cases have been described of recurrence of symptoms or progression to chronic disease, but these

Löfgren's syndrome is a rare disease that is often misdiagnosed or under diagnosed. The constellation of symptoms of erythema nodosum, acute polyarthritis (most commonly bilaterally in ankle and under 2 months since time of onset) as well as hilar lymphadenopathy in a young patient (under 40 years of age) should raise very high suspicions for this disease. Prompt recognition and treatment of this

disease can save much stress and pain for patients afflicted by it.

The authors declare no conflict of interest.

or hydroxychloroquine can also be used, and infiximab beyond that [36].

#### *Löfgren's Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97154*

syndrome itself does not cause arthritis, but is associated with rheumatoid arthritis, IBD and Behcet syndrome, all of which can cause arthritis. Sweet syndrome is associated with a characteristic rash that present as erythematous plaques, which should be differentiated from erythema nodosum. Neither condition is associated with hilar lymphadenopathy, thus chest radiography should be obtained to distinguish them from Löfgren's syndrome.

#### **8. Treatment/management**

Löfgren's syndrome is largely a self-limited disease, the erythema nodosum, acute polyarthritis and hilar lymphadenopathy resolves usually within a few weeks to months, most cases resolve within 1 year. Polyarthritis has been known to last up to 2 years. Treatment is largely supportive and goal is symptomatic control. NSAIDs are first line for anti-inflammatory properties to ameliorate discomfort of fever, erythema nodosum and arthritis; colchcine can also be used for this purpose. In severe or refractory cases, glucocorticoids can be used, which needs to be tapered off of once symptoms have been resolved. Further interventions with methotrexate or hydroxychloroquine can also be used, and infiximab beyond that [36].

#### **9. Prognosis**

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

Many conditions and diseases can cause erythema nodosum, polyarthritis and associated fever. These including: infections, drug reactions, malignancies, inflammatory bowel disease and other rheumatologic conditions. While chest radiograph with findings of hilar adenopathy can significantly increase specificity for Löfgren's syndrome, it is not always necessary and a detailed history and physical should be able to differentiate many of the other differential diagnoses

A wide variety of infections can cause erythema nodosum and arthritis, which can manifest as reactive arthritis or infectious arthritis. These include bacterial: streptococcous, chalymdia, yersinina, salmonella, campylobacter and tubcerculosis. Fungal: coccidiomycosis, histoplasmosis, blastomycosis. Viral: hepatitis B and infectious mononucleosis. Reactive and infectious arthritis generally present initially in the knee joint, which can overlap with Löfgren's syndrome, and the arthritis are also usually self-limited and acute. Therefore it can be difficult to distinguish between the two without chest radiography, but presence of hilar lymphadenopathy should exclude most of the infections listed above. The exception to this is tuberculosis, which can also present with hilar adenopathy, thus it is necessary to obtain tuberculosis skin or interferon-gamma testing to rule out tuberculosis infection.

Drug reactions that can cause erythema nodosum include: oral contraceptives, penicillins, sulfonamides, bromides, iodides and TNF Alpha inhibitors. Though drug reactions can cause fever, very rarely do they cause arthritis. Cessation of offending drug also often resolves symptoms. Thus, if there is no presence of acute polyarthritis, distinguishing a drug reaction from Löfgren's syndrome is clear.

Malignancies that can cause erythema nodosum include lymphoma, leukemia and carcinomas. These malignancies can also be associated with fever, but also very rarely cause arthritis. They can, however, cause hilar lymphadenopathy, thus it is

Ulcerative colitis and Crohns disease can cause erythema nodosum with associated fever as well as enteropathic arthritis. Enteropathic arthritis can present sporadically and intermittently, and can be mistaken for acute polyarthritis. Therefore, it is difficult to distinguish between inflammatory bowel disease and Löfgren's syndrome, chest radiography should be obtained to detect for presence of

Rheumatologic conditions such as Behcet disease and Sweet syndrome can also cause erythema nodosum, arthritis with associated fevers. Behcet syndrome causes polyarthritis of lower extremity joints, very similar to Löfgren's syndrome. Sweet

hilar adenopathy. IBD generally does not cause hilar lymphadenopathy.

important to delineate presence of acute polyarthritis.

**7.4 Inflammatory bowel disease (IBD)**

**7.5 Other rheumatologic conditions**

**7. Differential diagnoses**

listed below.

**7.1 Infections**

**7.2 Drug reactions**

**7.3 Malignancies**

**28**

Prognosis of Löfgren's syndrome is excellent; most patients achieve complete resolution of symptoms without recurrence in 6 months to 2 years. Cases have been described of recurrence of symptoms or progression to chronic disease, but these are exceedingly rare [35].

#### **10. Conclusions**

Löfgren's syndrome is a rare disease that is often misdiagnosed or under diagnosed. The constellation of symptoms of erythema nodosum, acute polyarthritis (most commonly bilaterally in ankle and under 2 months since time of onset) as well as hilar lymphadenopathy in a young patient (under 40 years of age) should raise very high suspicions for this disease. Prompt recognition and treatment of this disease can save much stress and pain for patients afflicted by it.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

### **Author details**

Shiyu Wang1 \* and Shailendra Singh<sup>2</sup>

1 White River Health System, Batesville, AR, USA

2 Unity Healthy System, Searcy, AR, USA

\*Address all correspondence to: shiyuwang0@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**31**

*Löfgren's Syndrome*

**References**

9110911.

9012596.

*DOI: http://dx.doi.org/10.5772/intechopen.97154*

Am J Respir Crit Care Med. 2007;175(1):40-44. doi:10.1164/

[9] Sato H, Grutters JC, Pantelidis P, Mizzon AN, Ahmad T, Van Houte AJ, Lammers JW, Van Den Bosch JM, Welsh KI, Du Bois RM. HLA-DQB1\*0201: a marker for good

prognosis in British and Dutch patients with sarcoidosis. Am J Respir Cell Mol Biol. 2002 Oct;27(4):406-412. doi: 10.1165/rcmb.4782. PMID: 12356573.

[10] Grunewald J, Eklund A. Löfgren's syndrome: human leukocyte antigen strongly influences the disease course. Am J Respir Crit Care Med. 2009 Feb 15;179(4):307-312. doi: 10.1164/

rccm.200807-1082OC. Epub 2008 Nov 7.

[11] Spagnolo P, Renzoni EA, Wells AU, Sato H, Grutters JC, Sestini P, Abdallah A, Gramiccioni E, Ruven HJ, du Bois RM, Welsh KI. C-C chemokine receptor 2 and sarcoidosis: association with Lofgren's syndrome. Am J Respir Crit Care Med. 2003 Nov 15;168(10):1162-1166. doi: 10.1164/rccm.200303-456OC. Epub 2003

[12] Kremer JM. Histologic findings in siblings with acute sarcoid arthritis: association with the B8,DR3 phenotype. J Rheumatol. 1986 Jun;13(3):593-597.

Rossman MD, Bresnitz EA, Terrin ML, Moller DR, Barnard J, Baughman RP, DePalo L, Hunninghake G, Johns C,

McLennan G, Newman LS, Rabin DL, Rose C, Teirstein AS, Weinberger SE, Yeager H, Cherniack R; ACCESS

Research Group. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med. 2001 Dec

[13] Rybicki BA, Iannuzzi MC, Frederick MM, Thompson BW,

Judson MA, Knatterud GL,

rccm.200608-1197OC

PMID: 18996998.

Jul 25. PMID: 12882757.

PMID: 3488404.

[1] Thomas KW, Hunninghake GW. Sarcoidosis. JAMA. 2003 Jun 25;289(24):3300-3303. doi: 10.1001/ jama.289.24.3300. PMID: 12824213.

[2] Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med. 1997 Apr 24;336(17):1224-34. doi: 10.1056/ NEJM199704243361706. Erratum in: N Engl J Med 1997 Jul 10;337(2):139. PMID:

[3] Arkema EV, Cozier YC. Epidemiology of sarcoidosis: current findings and future directions. *Ther Adv Chronic Dis*. 2018;9(11):227-240. Published 2018 Aug 24. doi:10.1177/2040622318790197

[4] Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, Iannuzzi MC. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Epidemiol. 1997 Feb

[5] Baughman RP, Lower EE, du Bois RM.

1;145(3):234-241. doi: 10.1093/ oxfordjournals.aje.a009096. PMID:

Sarcoidosis. Lancet. 2003 Mar 29;361(9363):1111-1118. doi: 10.1016/ S0140-6736(03)12888-7. PMID: 12672326.

[6] Visser H, Vos K, Zanelli E,

Löfgren's syndrome: Clinical,

2019 Oct 11. PMID: 31606494.

Verduyn W, Schreuder GM, Speyer I, Breedveld FC, Hazes JM. Sarcoid arthritis: clinical characteristics,

diagnostic aspects, and risk factors. Ann Rheum Dis. 2002 Jun;61(6):499-504. doi: 10.1136/ard.61.6.499. PMID: 12006321; PMCID: PMC1754119.

[7] Rubio-Rivas M, Franco J, Corbella X. Sarcoidosis presenting with and without

radiological and behavioral differences observed in a group of 691patients. Joint Bone Spine. 2020 Mar;87(2):141-147. doi: 10.1016/j.jbspin.2019.10.001. Epub

[8] Grunewald J, Eklund A. Sex-specific manifestations of Löfgren's syndrome.

### **References**

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

**30**

**Author details**

\* and Shailendra Singh<sup>2</sup>

1 White River Health System, Batesville, AR, USA

\*Address all correspondence to: shiyuwang0@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Unity Healthy System, Searcy, AR, USA

provided the original work is properly cited.

Shiyu Wang1

[1] Thomas KW, Hunninghake GW. Sarcoidosis. JAMA. 2003 Jun 25;289(24):3300-3303. doi: 10.1001/ jama.289.24.3300. PMID: 12824213.

[2] Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med. 1997 Apr 24;336(17):1224-34. doi: 10.1056/ NEJM199704243361706. Erratum in: N Engl J Med 1997 Jul 10;337(2):139. PMID: 9110911.

[3] Arkema EV, Cozier YC. Epidemiology of sarcoidosis: current findings and future directions. *Ther Adv Chronic Dis*. 2018;9(11):227-240. Published 2018 Aug 24. doi:10.1177/2040622318790197

[4] Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, Iannuzzi MC. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Epidemiol. 1997 Feb 1;145(3):234-241. doi: 10.1093/ oxfordjournals.aje.a009096. PMID: 9012596.

[5] Baughman RP, Lower EE, du Bois RM. Sarcoidosis. Lancet. 2003 Mar 29;361(9363):1111-1118. doi: 10.1016/ S0140-6736(03)12888-7. PMID: 12672326.

[6] Visser H, Vos K, Zanelli E, Verduyn W, Schreuder GM, Speyer I, Breedveld FC, Hazes JM. Sarcoid arthritis: clinical characteristics, diagnostic aspects, and risk factors. Ann Rheum Dis. 2002 Jun;61(6):499-504. doi: 10.1136/ard.61.6.499. PMID: 12006321; PMCID: PMC1754119.

[7] Rubio-Rivas M, Franco J, Corbella X. Sarcoidosis presenting with and without Löfgren's syndrome: Clinical, radiological and behavioral differences observed in a group of 691patients. Joint Bone Spine. 2020 Mar;87(2):141-147. doi: 10.1016/j.jbspin.2019.10.001. Epub 2019 Oct 11. PMID: 31606494.

[8] Grunewald J, Eklund A. Sex-specific manifestations of Löfgren's syndrome.

Am J Respir Crit Care Med. 2007;175(1):40-44. doi:10.1164/ rccm.200608-1197OC

[9] Sato H, Grutters JC, Pantelidis P, Mizzon AN, Ahmad T, Van Houte AJ, Lammers JW, Van Den Bosch JM, Welsh KI, Du Bois RM. HLA-DQB1\*0201: a marker for good prognosis in British and Dutch patients with sarcoidosis. Am J Respir Cell Mol Biol. 2002 Oct;27(4):406-412. doi: 10.1165/rcmb.4782. PMID: 12356573.

[10] Grunewald J, Eklund A. Löfgren's syndrome: human leukocyte antigen strongly influences the disease course. Am J Respir Crit Care Med. 2009 Feb 15;179(4):307-312. doi: 10.1164/ rccm.200807-1082OC. Epub 2008 Nov 7. PMID: 18996998.

[11] Spagnolo P, Renzoni EA, Wells AU, Sato H, Grutters JC, Sestini P, Abdallah A, Gramiccioni E, Ruven HJ, du Bois RM, Welsh KI. C-C chemokine receptor 2 and sarcoidosis: association with Lofgren's syndrome. Am J Respir Crit Care Med. 2003 Nov 15;168(10):1162-1166. doi: 10.1164/rccm.200303-456OC. Epub 2003 Jul 25. PMID: 12882757.

[12] Kremer JM. Histologic findings in siblings with acute sarcoid arthritis: association with the B8,DR3 phenotype. J Rheumatol. 1986 Jun;13(3):593-597. PMID: 3488404.

[13] Rybicki BA, Iannuzzi MC, Frederick MM, Thompson BW, Rossman MD, Bresnitz EA, Terrin ML, Moller DR, Barnard J, Baughman RP, DePalo L, Hunninghake G, Johns C, Judson MA, Knatterud GL, McLennan G, Newman LS, Rabin DL, Rose C, Teirstein AS, Weinberger SE, Yeager H, Cherniack R; ACCESS Research Group. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med. 2001 Dec

1;164(11):2085-2091. doi: 10.1164/ ajrccm.164.11.2106001. PMID: 11739139.

[14] Balmes JR, Abraham JL, Dweik RA, Fireman E, Fontenot AP, Maier LA, Muller-Quernheim J, Ostiguy G, Pepper LD, Saltini C, Schuler CR, Takaro TK, Wambach PF; ATS Ad Hoc Committee on Beryllium Sensitivity and Chronic Beryllium Disease. An official American Thoracic Society statement: diagnosis and management of beryllium sensitivity and chronic beryllium disease. Am J Respir Crit Care Med. 2014 Nov 15;190(10):e34-e59. doi: 10.1164/ rccm.201409-1722ST. PMID: 25398119.

[15] Werfel U, Schneider J, Rödelsperger K, Kotter J, Popp W, Woitowitz HJ, Zieger G. Sarcoid granulomatosis after zirconium exposure with multiple organ involvement. Eur Respir J. 1998 Sep;12(3):750. doi: 10.1183/09031936.98.12030750. PMID: 9762810.

[16] Cai HR, Cao M, Meng FQ, Wei JY. Pulmonary sarcoid-like granulomatosis induced by aluminum dust: report of a case and literature review. Chin Med J (Engl). 2007 Sep 5;120(17):1556-1560. PMID: 17908469.

[17] Izbicki G, Chavko R, Banauch GI, Weiden MD, Berger KI, Aldrich TK, Hall C, Kelly KJ, Prezant DJ. World Trade Center "sarcoid-like" granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest. 2007 May;131(5):1414-1423. doi: 10.1378/chest.06-2114. Epub 2007 Mar 30. PMID: 17400664.

[18] Ferrara G, Valentini D, Rao M, Wahlström J, Grunewald J, Larsson LO, Brighenti S, Dodoo E, Zumla A, Maeurer M. Humoral immune profiling of mycobacterial antigen recognition in sarcoidosis and Löfgren's syndrome using high-content peptide microarrays. Int J Infect Dis. 2017 Mar;56:167-175. doi: 10.1016/j.ijid.2017.01.021. Epub 2017 Jan 31. PMID: 28159576.

[19] Ishige I, Eishi Y, Takemura T, Kobayashi I, Nakata K, Tanaka I, Nagaoka S, Iwai K, Watanabe K, Takizawa T, Koike M. Propionibacterium acnes is the most common bacterium commensal in peripheral lung tissue and mediastinal lymph nodes from subjects without sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2005 Mar;22(1):33-42. PMID: 15881278.

[20] Saboor SA, Johnson NM, McFadden J. Detection of mycobacterial DNA in sarcoidosis and tuberculosis with polymerase chain reaction. Lancet. 1992 Apr 25;339(8800):1012-1015. doi: 10.1016/0140-6736(92)90535-b. PMID: 1349051.

[21] Burke WM, Keogh A, Maloney PJ, Delprado W, Bryant DH, Spratt P. Transmission of sarcoidosis via cardiac transplantation. Lancet. 1990 Dec 22-29;336(8730):1579. doi: 10.1016/0140- 6736(90)93354-r. PMID: 1979389.

[22] Bhagat R, Rizzieri DA, Vredenburgh JJ, Chao NJ, Folz RJ. Pulmonary sarcoidosis following stem cell transplantation: is it more than a chance occurrence? Chest. 2004 Aug;126(2):642-644. doi: 10.1378/ chest.126.2.642. PMID: 15302757.

[23] Ionescu DN, Hunt JL, Lomago D, Yousem SA. Recurrent sarcoidosis in lung transplant allografts: granulomas are of recipient origin. Diagn Mol Pathol. 2005 Sep;14(3):140-145. doi: 10.1097/01.pas.0000176765.26047.6f. PMID: 16106194.

[24] Sakthivel P, Bruder D. Mechanism of granuloma formation in sarcoidosis. Curr Opin Hematol. 2017 Jan;24(1):59-65. doi: 10.1097/MOH.0000000000000301. PMID: 27755127.

[25] Broos CE, Hendriks RW, Kool M. T-cell immunology in sarcoidosis: Disruption of a delicate balance between helper and regulatory T-cells. Curr Opin Pulm Med. 2016 Sep;22(5):476-483. doi:

**33**

*Löfgren's Syndrome*

PMID: 27379969.

*DOI: http://dx.doi.org/10.5772/intechopen.97154*

in various organs. Radiographics. 2004 Jan-Feb;24(1):87-104. doi: 10.1148/ rg.241035076. PMID: 14730039.

Springmeyer SC. Bronchoalveolar lavage cell populations in the diagnosis of sarcoidosis. Chest. 1993 Aug;104(2):352- 361. doi: 10.1378/chest.104.2.352. PMID:

[34] Winterbauer RH, Lammert J, Selland M, Wu R, Corley D,

[35] Sejdic A, Graudal N, Baslund B. Clinical and biochemical presentation of sarcoidosis with high and normal serum angiotensin-converting enzyme. Scand J Rheumatol. 2018 Nov;47(6):487-490. doi: 10.1080/03009742.2017.1420818. Epub 2018 Jun 22. PMID: 29929412.

[36] Zisman DA, Shorr AF, Lynch JP 3rd. Sarcoidosis involving the musculoskeletal system. Semin Respir Crit Care Med. 2002 Dec;23(6):555-570. doi: 10.1055/s-

2002-36520. PMID: 16088651.

8339618.

[26] Judson MA. The Clinical Features of Sarcoidosis: A Comprehensive Review. Clin Rev Allergy Immunol. 2015 Aug;49(1):63-78. doi: 10.1007/s12016-

10.1097/MCP.0000000000000303.

014-8450-y. PMID: 25274450.

[27] Kunz M, Beutel S, Bröcker E. Leucocyte activation in erythema nodosum. Clin Exp Dermatol. 1999 Sep;24(5):396-401. doi: 10.1046/j.1365- 2230.1999.00511.x. PMID: 10564331.

[28] Ponhold W. Das Löfgren-Syndrom: Die akute Form der Sarkoidose [The Löfgren syndrome: acute sarcoidosis (author's transl)]. Rontgenblatter. 1977 Jun;30(6):325-7. German. PMID: 897518.

[29] Roberto J. Barrios, Chapter 17 - Other Interstitial Lung Diseases, Editor(s): Dani S. Zander, Carol F. Farver, In The Foundations in Diagnostic Pathology Series, Pulmonary Pathology, Churchill Livingstone, 2008, Pages 348-373, ISBN 9780443067419, https://doi.org/10.1016/

B978-0-443-06741-9.50023-9.

[30] Visser H, Vos K, Zanelli E, et al. Sarcoid arthritis: clinical characteristics, diagnostic aspects, and risk factors. Ann

Rheum Dis. 2002;61(6):499-504.

[31] Johard U, Eklund A. Recurrent Löfgren's syndrome in three patients with sarcoidosis. Sarcoidosis. 1993 Sep;10(2):125-127. PMID: 8140298.

[32] MAYOCK RL, BERTRAND P, MORRISON CE, SCOTT JH.

[33] Koyama T, Ueda H, Togashi K, Umeoka S, Kataoka M, Nagai S.

Radiologic manifestations of sarcoidosis

MANIFESTATIONS OF SARCOIDOSIS. ANALYSIS OF 145 PATIENTS, WITH A REVIEW OF NINE SERIES SELECTED FROM THE LITERATURE. Am J Med. 1963 Jul;35:67-89. doi: 10.1016/0002- 9343(63)90165-7. PMID: 14046006.

doi:10.1136/ard.61.6.499

10.1097/MCP.0000000000000303. PMID: 27379969.

*Rare Diseases - Diagnostic and Therapeutic Odyssey*

[19] Ishige I, Eishi Y, Takemura T, Kobayashi I, Nakata K, Tanaka I, Nagaoka S, Iwai K, Watanabe K,

PMID: 15881278.

1349051.

[20] Saboor SA, Johnson NM,

Takizawa T, Koike M. Propionibacterium acnes is the most common bacterium commensal in peripheral lung tissue and mediastinal lymph nodes from subjects without sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2005 Mar;22(1):33-42.

McFadden J. Detection of mycobacterial DNA in sarcoidosis and tuberculosis with polymerase chain reaction. Lancet. 1992 Apr 25;339(8800):1012-1015. doi: 10.1016/0140-6736(92)90535-b. PMID:

[21] Burke WM, Keogh A, Maloney PJ, Delprado W, Bryant DH, Spratt P. Transmission of sarcoidosis via cardiac transplantation. Lancet. 1990 Dec 22-29;336(8730):1579. doi: 10.1016/0140- 6736(90)93354-r. PMID: 1979389.

[23] Ionescu DN, Hunt JL, Lomago D, Yousem SA. Recurrent sarcoidosis in lung transplant allografts: granulomas are of recipient origin. Diagn Mol Pathol. 2005 Sep;14(3):140-145. doi: 10.1097/01.pas.0000176765.26047.6f.

[24] Sakthivel P, Bruder D. Mechanism of granuloma formation in sarcoidosis. Curr Opin Hematol. 2017 Jan;24(1):59-65. doi: 10.1097/MOH.0000000000000301.

[25] Broos CE, Hendriks RW, Kool M. T-cell immunology in sarcoidosis: Disruption of a delicate balance between helper and regulatory T-cells. Curr Opin Pulm Med. 2016 Sep;22(5):476-483. doi:

[22] Bhagat R, Rizzieri DA, Vredenburgh JJ, Chao NJ, Folz RJ. Pulmonary sarcoidosis following stem cell transplantation: is it more than a chance occurrence? Chest. 2004 Aug;126(2):642-644. doi: 10.1378/ chest.126.2.642. PMID: 15302757.

PMID: 16106194.

PMID: 27755127.

1;164(11):2085-2091. doi: 10.1164/ ajrccm.164.11.2106001. PMID: 11739139.

[14] Balmes JR, Abraham JL, Dweik RA, Fireman E, Fontenot AP, Maier LA, Muller-Quernheim J, Ostiguy G, Pepper LD, Saltini C, Schuler CR, Takaro TK, Wambach PF; ATS Ad Hoc Committee on Beryllium Sensitivity and Chronic Beryllium Disease. An official American Thoracic Society statement: diagnosis and management of beryllium sensitivity and chronic beryllium

disease. Am J Respir Crit Care Med. 2014 Nov 15;190(10):e34-e59. doi: 10.1164/ rccm.201409-1722ST. PMID: 25398119.

granulomatosis after zirconium exposure with multiple organ involvement. Eur Respir J. 1998 Sep;12(3):750. doi: 10.1183/09031936.98.12030750. PMID:

[16] Cai HR, Cao M, Meng FQ, Wei JY. Pulmonary sarcoid-like granulomatosis induced by aluminum dust: report of a case and literature review. Chin Med J (Engl). 2007 Sep 5;120(17):1556-1560.

[17] Izbicki G, Chavko R, Banauch GI, Weiden MD, Berger KI, Aldrich TK, Hall C, Kelly KJ, Prezant DJ. World Trade Center "sarcoid-like" granulomatous pulmonary disease in New York City Fire Department rescue workers. Chest. 2007 May;131(5):1414-1423. doi: 10.1378/chest.06-2114. Epub 2007 Mar

[18] Ferrara G, Valentini D, Rao M, Wahlström J, Grunewald J, Larsson LO,

Maeurer M. Humoral immune profiling of mycobacterial antigen recognition in sarcoidosis and Löfgren's syndrome using high-content peptide microarrays. Int J Infect Dis. 2017 Mar;56:167-175. doi: 10.1016/j.ijid.2017.01.021. Epub 2017 Jan 31. PMID: 28159576.

Brighenti S, Dodoo E, Zumla A,

[15] Werfel U, Schneider J,

9762810.

PMID: 17908469.

30. PMID: 17400664.

Rödelsperger K, Kotter J, Popp W, Woitowitz HJ, Zieger G. Sarcoid

**32**

[26] Judson MA. The Clinical Features of Sarcoidosis: A Comprehensive Review. Clin Rev Allergy Immunol. 2015 Aug;49(1):63-78. doi: 10.1007/s12016- 014-8450-y. PMID: 25274450.

[27] Kunz M, Beutel S, Bröcker E. Leucocyte activation in erythema nodosum. Clin Exp Dermatol. 1999 Sep;24(5):396-401. doi: 10.1046/j.1365- 2230.1999.00511.x. PMID: 10564331.

[28] Ponhold W. Das Löfgren-Syndrom: Die akute Form der Sarkoidose [The Löfgren syndrome: acute sarcoidosis (author's transl)]. Rontgenblatter. 1977 Jun;30(6):325-7. German. PMID: 897518.

[29] Roberto J. Barrios, Chapter 17 - Other Interstitial Lung Diseases, Editor(s): Dani S. Zander, Carol F. Farver, In The Foundations in Diagnostic Pathology Series, Pulmonary Pathology, Churchill Livingstone, 2008, Pages 348-373, ISBN 9780443067419, https://doi.org/10.1016/ B978-0-443-06741-9.50023-9.

[30] Visser H, Vos K, Zanelli E, et al. Sarcoid arthritis: clinical characteristics, diagnostic aspects, and risk factors. Ann Rheum Dis. 2002;61(6):499-504. doi:10.1136/ard.61.6.499

[31] Johard U, Eklund A. Recurrent Löfgren's syndrome in three patients with sarcoidosis. Sarcoidosis. 1993 Sep;10(2):125-127. PMID: 8140298.

[32] MAYOCK RL, BERTRAND P, MORRISON CE, SCOTT JH. MANIFESTATIONS OF SARCOIDOSIS. ANALYSIS OF 145 PATIENTS, WITH A REVIEW OF NINE SERIES SELECTED FROM THE LITERATURE. Am J Med. 1963 Jul;35:67-89. doi: 10.1016/0002- 9343(63)90165-7. PMID: 14046006.

[33] Koyama T, Ueda H, Togashi K, Umeoka S, Kataoka M, Nagai S. Radiologic manifestations of sarcoidosis in various organs. Radiographics. 2004 Jan-Feb;24(1):87-104. doi: 10.1148/ rg.241035076. PMID: 14730039.

[34] Winterbauer RH, Lammert J, Selland M, Wu R, Corley D, Springmeyer SC. Bronchoalveolar lavage cell populations in the diagnosis of sarcoidosis. Chest. 1993 Aug;104(2):352- 361. doi: 10.1378/chest.104.2.352. PMID: 8339618.

[35] Sejdic A, Graudal N, Baslund B. Clinical and biochemical presentation of sarcoidosis with high and normal serum angiotensin-converting enzyme. Scand J Rheumatol. 2018 Nov;47(6):487-490. doi: 10.1080/03009742.2017.1420818. Epub 2018 Jun 22. PMID: 29929412.

[36] Zisman DA, Shorr AF, Lynch JP 3rd. Sarcoidosis involving the musculoskeletal system. Semin Respir Crit Care Med. 2002 Dec;23(6):555-570. doi: 10.1055/s-2002-36520. PMID: 16088651.

**35**

Section 3

Rare Neoplastic Diseases

Section 3
