We compared the clinical and genetic features of FMF with the main parameter of the age of onset. We found that in patients with late-onset of disease, the disease presentation is milder and more atypical. Similar studies are summarized in Table 4.
Table 4
Previous studies comparing the clinical and genetic features of early and late-onset FMF patients
| Sayarlioglu et al. (≥ 20 y vs. <20 y) Turkey (54) | Ureten et al. (> 20 y vs. ≤20 y) Turkey (104) | Yasar Bilge et al. (> 20 y vs. ≤20 y) Turkey (109) | Tamir et al. (≥ 40 y vs. <40 y) Israel (105) | Kriegshauser et al. (≥ 40 y vs. <40 y) Armenia (106) | Endo et al. (≥ 40 y vs. <20 y) Japan (107) | Kishida et al. (≥ 40 y vs. <20 y) Japan (108) |
Patient count | 401 | 260 | 2246 | 4000 | 10370 | 387 | 292 |
Late onset patient count and percentage | 57, 14% (≥ 40 y: 5, %1,2) | 77, 30% (≥ 40 y: 0, %0) | 613, 27.3% | 20, %0,5 | 354, %3,4 | 90, %23,2 | 44, %15,1 |
Gender (M:F) | 1.1:1 vs. 1:1.1 | | 1: 11 vs. 1:1.1 | 4:1 vs. 1.5:1 | 1:1.2 vs. 1.1:1 | 1:1.4 vs. 1:1.7 | 1:1.3 vs. 1:2.1 |
Mean delay in diagnosis | 11.2 ± 8.8 vs. 12.1 ± 9 | 7.25 ± 5.83 vs. 10.3 ± 9.8 P = 0.003 | 3(1–9) vs. 10(3–8) P = 0.001 | 4.9 ± 5.8 vs. 20 ± 13 P < 0.001 | | 2(0.5-8) vs. 7(2–15) P < 0.001 | 3(0–28) vs. 12(0.69) P < 0.001 |
Fever % | 94.7 vs. 96.2 | 89.6 vs. 90.7 | 86.8 vs. 93.8 P < 0.001 | 5 vs. 30 P < 0.001 | 89.5 vs. 92.5 P = 0.04 | | 97.7 vs. 99.2 |
Abdominal Pain % | 94.7 vs. 92.4 | 92.2 vs. 91.8 | 91 vs. 96 P < 0.001 | 100 vs. 92.5 | 90.4 vs. 86.3 P = 0.03 | 30 vs. 64 P < 0.001 | 40.9 vs. 67.2 P = 0.002 |
Chest Pain % | 43.9 vs. 54.7 | 25.8 vs. 36..6 | 38.3 vs. 51.4 P < 0.001 | 5 vs. 45 P < 0.001 | 43.2 vs. 48.6 P = 0.04 | 24 vs. 45 P = 0.002 | 25 vs. 52.3 P = 0.002 |
Arthritis % | 42.1 vs. 64.5 P = 0.001 | 33.8 vs. 48.6 P = 0.02 | 30.2 vs. 43.5 P < 0.001 | 10 vs. 78 P < 0.001 | 17.5 vs. 16.8 | 62 vs. 32 P < 0.001 | 45.5 vs. 41.4 |
Myalgia % | | | 13.2 vs. 13 | | | 26 vs. 8 P = 0.005 | 15.9 vs. 18 |
ELE % | 7 vs. 17.4 P = 0.004 | 19.5 vs. 32.4 P = 0.03 | 15.2 vs. 26.9 P < 0.001 | 15 vs. 20 | 9.9 vs. 15 P = 0.009 | 19 vs. 10 | |
Amyloidosis % | 3.5 vs. 5.8 | 0 vs. 3.8 | 8.2 vs. 8.8 | | 0.56 vs. 0.61 | 3 vs. 1 | |
Family history % | 57.9 vs. 55.5 | | 53 vs. 59 P = 0.003 | 65 vs. 72.5 | 29.9 vs. 34 | 12 vs. 28 P = 0.018 | 6.8 vs. 28.9 P = 0.012 |
Colchicine response | 98.2 vs. 96.8 | | | 100 vs. 82.5 | | 97 vs. 98 | 95.1 vs. 94.7 |
M694V homozygous mutation % | | | 11.6 vs. 20.9 P < 0,001 | | 3.3 vs. 11.4 P < 0.001 | | |
In our study, both in the above 40-year group and below 20-year group included 63,4% of female patients. This ratio is similar to the 2020 patients followed in our clinic in 2008–2017 in which 62.1% of the patients are female. This similarity prevents a potential gender-based confounding factor. The gender ratio of our study is similar to previous studies (11, 12).
Delay in diagnosis is common in FMF. In our study delay in Group 1 was 5.6 ± 5.75 and in Group 2 was 10.7 ± 12.39, this difference was found significant (p = 0.013). Furthermore, in the studies of Tamir et al. and Sayarlioglu et al. the delay was found significantly lower in late-onset patients (9, 13). This can be due to increased self-awareness among more aged patients. In addition, this means that there will be patients presenting to the clinic with non-specific FMF symptoms such as abdominal pain, fever, and joint pain. This study is valuable since it suggests the inclusion of FMF to the differential diagnosis of these complaints even if the patient is above 40 years old. Furthermore, as FMF is a disease diagnosed with history taking and physical exam only, it saves the institutions from expensive imaging techniques and blood tests to explain undiagnosed abdominal pain, fever or any symptom of FMF.
Regarding the clinical features, the only symptom with a significant difference was fever when comparing two groups. Fever was observed in 63.4% of the patients in group 1, and 81.7% of the patients in group 2 (p = 0.026). This difference hints at an atypical presentation at the late onset of the disease. Fever was also found to be more frequent in patients with disease onset before 40 years when compared to after 40 years in the study of Tamir et al (13). In an Armenian cohort with 10370 patients, fever was also found to be more frequent with earlier onset (14). Nevertheless, fever was also found to be the most common second symptom in group 1.
Homozygous M694V mutation in FMF is known to be associated with increased severity of the disease and amyloidosis development (12, 15). In our study, in group 1, 2 (5.3%) patients had a homozygous M694V mutation whereas 19 (26%) patients had it in group 2 (p = 0.008). In addition, the proportion of patients carrying at least a single copy of M694V mutation was also found significantly higher (0.03). Howbeit, group 1 had a higher exon 2 mutation ratio of 52.6% when compared to group 2 with a ratio of 31.5% (p = 0.03). In a study by Ureten et al. comparing M694V homozygous, heterozygous and other mutations, disease onset was found to be lower in relative order (12). Similar findings were presented in other studies (13, 14, 16). Our results are consistent with previous studies. Currently, mutations such as E148Q and R202Q are defined to be clinically unknown, even benign polymorphisms by some authors yet our findings on the frequency of these mutations in late-onset patients suggest its importance. Even though these patients are clinically milder, amyloidosis prevalence and hospital visit count were not found lower than early-onset patients. Therefore, further analysis of exon 2 mutations with larger cohorts is required.
Referring to colchicine treatment, the beginning dose, maximum colchicine dose, and colchicine response was similar in both groups. Our results are similar to two studies from Japan (17, 18). However, colchicine dose in the last 6 months was found significantly higher in early-onset patients (p = 0.04). Sayarlioglu et al. also found similar colchicine responses in both groups (9). Whereas, Tamir et al. found that despite low colchicine dose, late-onset patients had a better treatment response (13). The low colchicine dose in the last 6 months can be interpreted as mild disease severity. FMF is the disease of the innate immune system where an autoinflammation is the main explanation of the pathogenesis (1). The milder clinical presentation in patients with late-onset of FMF can be explained as the activity of the innate immune system declines with age (19).
The major limitation of our study was its retrospective design. In the meantime, due to its cohort including over 2000 patients, case-based missing data at chart reviews did not affect the overall results. Another limitation was the lack of patient numerical disease assessment. This challenged our evaluation of the disease severity nevertheless information on colchicine dose enhanced our understanding objectively. The lack of acute phase reactants might seem like a limitation, but FMF is a disease with a clinical diagnosis hence the laboratory values like acute phase reactants are not required. Our primary focus was on the age of diagnosis. Acute phase reactants are more valid during follow-ups to prevent amyloidosis development. The amyloidosis rate in our study was 1.6% which was already low when compared to previous studies where it was found to be approximately 10% (11, 15). The last limitation of our study was related to genetic analysis. We could not find the genetic information of 9,7% of the patients, yet the statistical analysis of the remaining data was still significant.