**3. Etiology**

Etiological factors for PR are under investigation and uncertain however intrinsic (gene mutations), extrinsic (external factor lifestyle and smoking) and idiopathic factors seem to be important in PR. Initially, it was believed that allergic agents and infectious agents may provoke the symptoms, but recent studies have shown that even the injection of histamine did not cause PR. It is thought that trauma, stress, anxiety, and cold can stimulate the flares of PR however recent data support the thought. Consumption of nitrate-containing food triggers PR [11].

Several etiological studies suggested that the mutated MEFV Gene seems to be an aggregating factor for the severity of PR [12]. According to Iranian research during the attack of PR level of C-reactive protein was increased in about 50%of cases. Erythrocyte sedimentation rate was also elevated during the attack of PR [13]. Anti-CCP antibodies level was also found high in PR patients [3, 14]. Another study showed that autoantibodies RF and anti-CCP concentration appear to be elevated in PR patients and is thought to be responsible for developing RA and other connective tissue diseases [15]. Further research conducted in PR patients also showed uplift RF concentration in 33.3% of patients and a high concentration of anti-CCP in 38.9% of patients. Another research showed the follow-up of 43 patients to other connective tissue diseases and of 28 patients to RA out of a total of 160 patients of PR [16, 17]. The recently high concentration of anti-CCP antibodies and anti-keratin was found in the patients of PR [11]. Studies have documented that ultrasonography of synovitis of PR patients showed a high concentration of ACPA antibodies in PR patients. These studies suggest the strong relationship between Anti-Cyclic Citrullinted Protein antibodies and Rheumatoid factor in PR and RA [17–19].

Another report has elucidated the role of the HLA Gene on Chromosome 6 which is thought to be responsible for about 30% of all cases of RA [20–22]. It is also reported that the HLA-DRB1 alleles encode for a shared epitope [10] which may be a risk factor for PR and RA [23]. Recent studies also showed a strong prevalence of HLA-DR shared epitope alleles in PR. The homozygosity of SE alleles in PR patients is responsible for the progress of half of the PR cases to RA. A Korean study showed a great prevalence of HLA-DRB1\*0803 and HLA-DRB1\*1302 in PR patients and these alleles are distinct in PR [24].

Many investigations have concluded that gene involvement in gene–environment interaction is not only one factor for a mutation in HLA-DRB1 but factors affecting gene linkage equilibrium may also cause variation in the gene [25].

**263**

**Figure 1.**

*Overviews of Palindromic rheumatism.*

*Palindromic Rheumatism: Biology and Treatment Options*

Other researchers have demonstrated the role of PADI4 (Protein-arginine deiminase type-4) which is a gene that encodes for enzymes that are responsible for the formation of Citrulline from arginine. It has recently been found that any effect in the stability of PADI4 results in a high level of Anti-CCP antibodies [26]. According to a Chinese study, periodic and episodic attacks of PR show a strong

TNFα (Tumor Necrosis factor) which are short-lived pro-inflammatory cytokines showed a strong relationship with PR. Another case study investigated TNFRSF1A and TNFRSF1B mutations in PR patients in the Chinese population [27, 28]. Another novel study has indicated that the concentration of cytokines like IL-6 and TNFα was elevated in synovium and serum of patients [29, 30]. It has been reported that TNFα microsatellite polymorphism indicates a close connection with the disease by its association with HLA-DRB1 SE. Autoinflammatory diseases like PR are caused by deregulation in inflammasome components [31]. According to Novel research, the PYCARD\ASC Splice variant has been found in PR patients. This inflammasome-associated mutation may be a risk factor for PR patients. According to this research exon2, PYCARD\ASC is more expressed in patients with PR. PYCARD\ASC mature IL-IB for innate immunity. The inflexibility of PYCARD\ASC leads to more secretions of IL-IB so the exon2 splice variant may be a risk factor for disease in PR patients [32]. The presence of conserved exon2 in DNA of all patients of PR, high amount of NLRP3 (Nucleotide-binding oligomerization domain, Leucine-rich Repeat, and Pyrin domain), and high concentration of IL-1B and IL-18 show the strong association between PR and this gene [33]. Comprehensive pathophysiology of Palindromic rheumatism has shown

Polymorphism in the promoter sequence of Stromelysin 1(MMB- gene) and HLA gene have been studied in recent years. Recent studies indicated a close

*DOI: http://dx.doi.org/10.5772/intechopen.96796*

link with PADI4 [18, 22, 26].

in **Figure 1**.

*Palindromic Rheumatism: Biology and Treatment Options DOI: http://dx.doi.org/10.5772/intechopen.96796*

*Genetic Variation*

**2. Epidemiology**

**3. Etiology**

A high concentration of Rheumatoid factor and Anti -CCP antibodies in both PR and RA strengthen the correlation between the two diseases. However, despite these similarities, PR is different from RA in that joints are free of symptoms between attacks. According to research attacks of PR usually affect one joint but other structures can be affected in 30% cases and Rheumatoid nodules also appear in one-third cases of PR. Time of attack is not definite however according to Research in London 50% of patients develop attack of PR in the late afternoon and some others at night time [7–9].

Indeed mounting studies highlight the frequency of PR is significantly lower than RA [9]. Epidemiological data from Canadian research suggest that females are most likely to develop PR than men in both conditions of Arthritis. However, it has

been estimated that the average age was 56 years in RA and 49 in PR [10].

Protein antibodies and Rheumatoid factor in PR and RA [17–19].

gene linkage equilibrium may also cause variation in the gene [25].

Another report has elucidated the role of the HLA Gene on Chromosome 6 which is thought to be responsible for about 30% of all cases of RA [20–22]. It is also reported that the HLA-DRB1 alleles encode for a shared epitope [10] which may be a risk factor for PR and RA [23]. Recent studies also showed a strong prevalence of HLA-DR shared epitope alleles in PR. The homozygosity of SE alleles in PR patients is responsible for the progress of half of the PR cases to RA. A Korean study showed a great prevalence of HLA-DRB1\*0803 and HLA-DRB1\*1302 in PR patients and

Many investigations have concluded that gene involvement in gene–environment interaction is not only one factor for a mutation in HLA-DRB1 but factors affecting

Etiological factors for PR are under investigation and uncertain however intrinsic (gene mutations), extrinsic (external factor lifestyle and smoking) and idiopathic factors seem to be important in PR. Initially, it was believed that allergic agents and infectious agents may provoke the symptoms, but recent studies have shown that even the injection of histamine did not cause PR. It is thought that trauma, stress, anxiety, and cold can stimulate the flares of PR however recent data support the thought. Consumption of nitrate-containing food triggers PR [11]. Several etiological studies suggested that the mutated MEFV Gene seems to be an aggregating factor for the severity of PR [12]. According to Iranian research during the attack of PR level of C-reactive protein was increased in about 50%of cases. Erythrocyte sedimentation rate was also elevated during the attack of PR [13]. Anti-CCP antibodies level was also found high in PR patients [3, 14]. Another study showed that autoantibodies RF and anti-CCP concentration appear to be elevated in PR patients and is thought to be responsible for developing RA and other connective tissue diseases [15]. Further research conducted in PR patients also showed uplift RF concentration in 33.3% of patients and a high concentration of anti-CCP in 38.9% of patients. Another research showed the follow-up of 43 patients to other connective tissue diseases and of 28 patients to RA out of a total of 160 patients of PR [16, 17]. The recently high concentration of anti-CCP antibodies and anti-keratin was found in the patients of PR [11]. Studies have documented that ultrasonography of synovitis of PR patients showed a high concentration of ACPA antibodies in PR patients. These studies suggest the strong relationship between Anti-Cyclic Citrullinted

**262**

these alleles are distinct in PR [24].

Other researchers have demonstrated the role of PADI4 (Protein-arginine deiminase type-4) which is a gene that encodes for enzymes that are responsible for the formation of Citrulline from arginine. It has recently been found that any effect in the stability of PADI4 results in a high level of Anti-CCP antibodies [26]. According to a Chinese study, periodic and episodic attacks of PR show a strong link with PADI4 [18, 22, 26].

TNFα (Tumor Necrosis factor) which are short-lived pro-inflammatory cytokines showed a strong relationship with PR. Another case study investigated TNFRSF1A and TNFRSF1B mutations in PR patients in the Chinese population [27, 28]. Another novel study has indicated that the concentration of cytokines like IL-6 and TNFα was elevated in synovium and serum of patients [29, 30]. It has been reported that TNFα microsatellite polymorphism indicates a close connection with the disease by its association with HLA-DRB1 SE. Autoinflammatory diseases like PR are caused by deregulation in inflammasome components [31]. According to Novel research, the PYCARD\ASC Splice variant has been found in PR patients. This inflammasome-associated mutation may be a risk factor for PR patients. According to this research exon2, PYCARD\ASC is more expressed in patients with PR. PYCARD\ASC mature IL-IB for innate immunity. The inflexibility of PYCARD\ASC leads to more secretions of IL-IB so the exon2 splice variant may be a risk factor for disease in PR patients [32]. The presence of conserved exon2 in DNA of all patients of PR, high amount of NLRP3 (Nucleotide-binding oligomerization domain, Leucine-rich Repeat, and Pyrin domain), and high concentration of IL-1B and IL-18 show the strong association between PR and this gene [33]. Comprehensive pathophysiology of Palindromic rheumatism has shown in **Figure 1**.

Polymorphism in the promoter sequence of Stromelysin 1(MMB- gene) and HLA gene have been studied in recent years. Recent studies indicated a close

**Figure 1.** *Overviews of Palindromic rheumatism.*


#### **Table 1.**

*Palindromic rheumatism and other relapsing diseases.*

association between MEFV and PR. Another research investigated that smoking and PTPN22 Showed an association with an increase in ACPA. It is also reported that PTPN22 (Protein Tyrosine Phosphatase Non-receptor Type 22) which encodes for protein tyrosine phosphate clearly shows an association of microsatellite STP PTPN22gene with rheumatism [34]. According to a Chinese report Anti-MCV (Anti Mutated Citrullinated Vimentin) antibodies have also been reported as a biomarker in patients with Rheumatoid Arthritis although their role in PR is not studied [35] (**Table 1**).

## **4. Environmental factors**

In recent year's association of periodontitis (PD) and PR association has been studied. PD is inflammation of periodontal tissues caused by red-complex bacteria i.e.*P.gingivalis* which affects the process of Citrullination by expressing peptidyl- arginine deiminase enzyme (PAD) [38]. According to research in Israel avoiding offending diet and intake of proper diet may affect the flares of PR. Smoking can also trigger the process of Citrullination by affecting the immune reactions of the HLA Gene [39]. Most of the case study reports that the onset of

**265**

**Figure 2.**

*Palindromic Rheumatism: Biology and Treatment Options*

PR frequently begins in the late afternoon and early morning [40, 41]. Several

It has been observed that certain types of food can trigger a periodic attack of Palindromic rheumatism and elimination of that type of food from the diet has resulted in a reduction of attacks. According to a clinical trial conducted for evaluation of the role that certain type of food can play in PR, patients show that patients who were offended to eat eggs, cheese, fish, and canned vegetables resulted in the complete cessation of attack, and those patients who were presented with these food show more reoccurrence of attack. Therefore, offending food should be avoided to reduce the occurrence of PR although this needs more research that

According to research in Japan, Anti-CPA in PR patients who developed RA was higher than those who did not develop RA in a future life [15]. According to a British case study of 39 patients of PR 19 showed progression to RA. Another study also indicated that most cases of PR progressed to other chronic arthritis and 35\60 progressed to RA [43]. The reason for this progression is multifactorial and one of the factors for this progression is a misdiagnosis of PR as there is no specific test and diagnosis is made mostly on physician's judgment and others may include progres-

sion duration which may vary from months to20 years [14, 44, 45].

factors responsible for the progression of PR as shown in **Figure 2**.

*Schematic representation of factors for development of Palindromic Rheumatism.*

**5. Palindromic rheumatism and diet**

**6. PR progression to RA**

which type of specific food should be avoided [4, 42].

*DOI: http://dx.doi.org/10.5772/intechopen.96796*

*Palindromic Rheumatism: Biology and Treatment Options DOI: http://dx.doi.org/10.5772/intechopen.96796*

*Genetic Variation*

Gout (Urate crystals deposing disease)

Arthritis associated with Bowel disease

Familial

Intermittent Hydrarthrosis

Relapsing polychondritis

**Table 1.**

Mediterranean fever

Reactive Arthritis Infections history in

**264**

(**Table 1**).

**4. Environmental factors**

association between MEFV and PR. Another research investigated that smoking and PTPN22 Showed an association with an increase in ACPA. It is also reported that PTPN22 (Protein Tyrosine Phosphatase Non-receptor Type 22) which encodes for protein tyrosine phosphate clearly shows an association of microsatellite STP PTPN22gene with rheumatism [34]. According to a Chinese report Anti-MCV (Anti Mutated Citrullinated Vimentin) antibodies have also been reported as a biomarker in patients with Rheumatoid Arthritis although their role in PR is not studied [35]

TRAPS Autosomal dominant TNF alpha [37]

**Disease Clinical characteristics Gene mutation References**

URAT1, GLUT-9 (Transporters) involvement

HLA-B27(In 80% of population)

HLA-B27(50–75% of population)

antibodies and

triglycerides

No inflammatory sign MEFV involvement [37]

malabsorption parameters

HLA-B27,NOD2, *ATG16L1* [37]

HLA-B51(10–80%) [37]

HLA-DRB1 Involvement [37]

MEFV mutation [37]

Nonspecific [37]

[36]

[37]

[37]

[37]

[37]

Presence of needle-like crystals in synovial fluid of joints

Gut inflammation,10%arthritis

caused by *Tropheryma whipplei*

possibility of erosive bone lesion

Hyperlipidemia Xanthomas High cholesterol and

Cartilaginous structure involves

Celiac disease Nonerosive arthritis Transglutaminase

Familial history, MEFV mutation, Chronic arthritis

neutrophils hyperfunction, inflammatory lesion

genitourinary and Gastrointestinal tract (GI)

precedes enteritis

Whipple's disease Weight loss, diarrhea, and fever

Sarcoidosis Granuloma formation and the

(5%)

only

*Palindromic rheumatism and other relapsing diseases.*

Behcet disease T cells abnormality and

In recent year's association of periodontitis (PD) and PR association has been studied. PD is inflammation of periodontal tissues caused by red-complex bacteria i.e.*P.gingivalis* which affects the process of Citrullination by expressing peptidyl- arginine deiminase enzyme (PAD) [38]. According to research in Israel avoiding offending diet and intake of proper diet may affect the flares of PR. Smoking can also trigger the process of Citrullination by affecting the immune reactions of the HLA Gene [39]. Most of the case study reports that the onset of

**Figure 2.** *Schematic representation of factors for development of Palindromic Rheumatism.*

PR frequently begins in the late afternoon and early morning [40, 41]. Several factors responsible for the progression of PR as shown in **Figure 2**.
