Terminology

Familial Mediterranean fever (FMF), the most common type of hereditary autoinflammatory disorders, is characterized by recurrent episodes of inflammation in serosal and synovial membranes and a tendency for secondary amyloidosis . FMF is more prevalent in Jews, Arabs, Armenians, and Turks, and analysis of the typical patients revealed an autosomal recessive mode of inheritance pattern . Variations in the MEFV gene encoding pyrin protein were identified through positional cloning in consanguineous families , and missense variations in the exon 10 of this gene were reported to be responsible for typical FMF phenotype . Disease-associated exon 10 variants have been associated with increased activation of inflammasome, a multiprotein platform regulating caspase 1 activity that leads to interleukin 1-beta (IL-1β) activation, which correlates with the number and penetrance of the MEFV variations .

Colchicine was shown to be effective in the prevention of recurrent inflammatory attacks and development of secondary amyloidosis in FMF , long before the identification of its genetic basis leading to autoinflammatory manifestations. Serendipity played a critical role in the discovery of colchicine’s efficacy in FMF, and its exact mechanism of action in FMF has yet to be clarified . Prophylactic efficacy of colchicine has not been observed in other hereditary periodic fever syndromes; therefore, response to colchicine became a critical component of the classification criteria as one of the distinctive features of FMF . Diagnosis of FMF is still based on clinical grounds , and response to colchicine provides a great help in differentiating those patients with typical clinical findings, even when there is a single or no exon 10 variation in the MEFV gene from other autoinflammatory conditions with overlapping clinical features .

Colchicine has been used as a potent anti-inflammatory drug in gout for ages despite its very narrow therapeutic window. Gastrointestinal and other adverse effects such as pain, nausea, and cramps limit its use at higher doses. Therefore, the prophylactic efficacy provided by tolerable doses of colchicine may not be adequate enough in a group of FMF patients with a more severe disease course. These patients are usually named as “colchicine-resistant” or “colchicine-refractory” FMF (cr-FMF) patients. However, a partial or complete response to colchicine response is an important feature of FMF , and colchicine resistance or no response to colchicine at all may suggest the diagnosis of other forms of hereditary autoinflammatory disorders, including mevalonate kinase deficiency (MVD), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), and cryopyrin-associated periodic syndrome (CAPS). Even some patients with MEFV gene variations, which are located at genomic regions other than exon 10, may have several atypical colchicine-refractory autoinflammatory manifestations, which are not compatible with the FMF phenotype, such as those patients with p.Ser242Arg in exon 2 or residue 577 variations in exon 8 . These patients can be classified within the spectrum of “pyrin-associated autoinflammatory disorders” but not as cr-FMF patients .

Therefore, it would be more appropriate to describe those patients with FMF phenotype and a severe disease course, whose manifestations could not be controlled enough with the highest tolerable doses of colchicine, as “inadequate responders.” This definition requires the confirmation of FMF diagnosis and assessment of disease severity as well as the assurance of effective use of colchicine, all of which are critical factors for approaching to an FMF patient with an inadequate response to colchicine ( Table 1 ).

Assessment of disease severity in FMF

FMF may run a variable course in terms of its severity, and the MEFV variations have been shown to be the most important factor affecting its inflammatory characteristics and phenotypic variability . Contributions of environmental factors and other modifier genes were estimated as 12% and 17% on an average, respectively .

Penetrance of the disease-associated MEFV variants, especially p.Met694Val, has been considered as the main factor determining the severity of inflammatory response, which affects the disease course and risk of developing complications . Colchicine requirement and the frequency of inadequate responders were reported to be higher in patients homozygous for p.Met694Val variant than those patients with other exon 10 variants or those patients with heterozygous or no MEFV mutation . Patients with a severe course are characterized by more frequent (1–2 times or more in a month) and longer attacks, involvement of more than one site during individual episodes, and ongoing acute-phase response in attack-free periods . Some of the disease features such as arthritis are known to be less responsive to colchicine treatment than other attack components , and other musculoskeletal manifestations such as exertional leg pain and vasculitis were also found to be associated with a more severe disease course .

FMF severity determined by strong influence of genetics is usually associated with an earlier disease onset and more persistent clinical findings. However, some patients may temporarily experience a relatively more severe or refractory period with the influences of psychogenic, hormonal, infectious, or other factors, and after control of their inflammatory findings with more effective treatments, they may run long periods of stable course with only effective doses of colchicine treatment. In this regard, it is necessary to note the contribution of environmental factors, especially infections as reflected by country-specific infant mortality rates, to disease severity and amyloidosis risk .

Organ damage associated with uncontrolled inflammatory response may also complicate the assessment of disease severity . A relatively severe disease course increases the risk of secondary amyloidosis and leads to the development of chronic sequelae with organ failures or growth retardation. However, development of amyloidosis might be due to delays in the diagnosis or poor compliance of the patients. Some of those patients may respond very well to colchicine treatment alone even after the development of amyloidosis and other complications .

Furthermore, in a subset of so-called “phenotype 2” patients, amyloidosis could be the first and only manifestation of the disease, and it may not be associated with the frequency, duration, or type of the inflammatory attacks of FMF . These patients may have additional genetic factors aggregating within the families, which may be associated with an earlier development of amyloidosis without FMF findings. This heterogeneous group of phenotype 2 patients may also include those with heterozygous MEFV variants and another inflammatory condition with an increased risk of amyloidosis such as ankylosing spondylitis . In these patients, MEFV variants may increase the susceptibility to other inflammatory conditions using shared pathogenic pathways , and risk of amyloidosis may be associated with the contribution of MEFV variants without developing any FMF-related manifestations.

It is important to differentiate the features of severe disease course from the treatment-refractory damages and to clarify the underlying causes of established damages such as amyloidosis for a better planning of the management of these patients with colchicine and biologic agents ( Tables 1 and 2 ).

Assessment of disease severity in FMF

FMF may run a variable course in terms of its severity, and the MEFV variations have been shown to be the most important factor affecting its inflammatory characteristics and phenotypic variability . Contributions of environmental factors and other modifier genes were estimated as 12% and 17% on an average, respectively .

Penetrance of the disease-associated MEFV variants, especially p.Met694Val, has been considered as the main factor determining the severity of inflammatory response, which affects the disease course and risk of developing complications . Colchicine requirement and the frequency of inadequate responders were reported to be higher in patients homozygous for p.Met694Val variant than those patients with other exon 10 variants or those patients with heterozygous or no MEFV mutation . Patients with a severe course are characterized by more frequent (1–2 times or more in a month) and longer attacks, involvement of more than one site during individual episodes, and ongoing acute-phase response in attack-free periods . Some of the disease features such as arthritis are known to be less responsive to colchicine treatment than other attack components , and other musculoskeletal manifestations such as exertional leg pain and vasculitis were also found to be associated with a more severe disease course .

FMF severity determined by strong influence of genetics is usually associated with an earlier disease onset and more persistent clinical findings. However, some patients may temporarily experience a relatively more severe or refractory period with the influences of psychogenic, hormonal, infectious, or other factors, and after control of their inflammatory findings with more effective treatments, they may run long periods of stable course with only effective doses of colchicine treatment. In this regard, it is necessary to note the contribution of environmental factors, especially infections as reflected by country-specific infant mortality rates, to disease severity and amyloidosis risk .

Organ damage associated with uncontrolled inflammatory response may also complicate the assessment of disease severity . A relatively severe disease course increases the risk of secondary amyloidosis and leads to the development of chronic sequelae with organ failures or growth retardation. However, development of amyloidosis might be due to delays in the diagnosis or poor compliance of the patients. Some of those patients may respond very well to colchicine treatment alone even after the development of amyloidosis and other complications .

Furthermore, in a subset of so-called “phenotype 2” patients, amyloidosis could be the first and only manifestation of the disease, and it may not be associated with the frequency, duration, or type of the inflammatory attacks of FMF . These patients may have additional genetic factors aggregating within the families, which may be associated with an earlier development of amyloidosis without FMF findings. This heterogeneous group of phenotype 2 patients may also include those with heterozygous MEFV variants and another inflammatory condition with an increased risk of amyloidosis such as ankylosing spondylitis . In these patients, MEFV variants may increase the susceptibility to other inflammatory conditions using shared pathogenic pathways , and risk of amyloidosis may be associated with the contribution of MEFV variants without developing any FMF-related manifestations.

It is important to differentiate the features of severe disease course from the treatment-refractory damages and to clarify the underlying causes of established damages such as amyloidosis for a better planning of the management of these patients with colchicine and biologic agents ( Tables 1 and 2 ).

Optimum use of colchicine and compliance

Colchicine has a prophylactic activity in FMF patients, and its efficacy can be observed when it is used regularly at stable doses. Colchicine treatment should aim to prevent both the recurrence of inflammatory episodes and the development of amyloidosis, and effective doses required for the latter goal may be higher . Colchicine is usually given at tolerable doses to children and adults , and the doses need to be adjusted according to the ongoing disease activity determined by number and burden of inflammatory episodes in every 3–6 months. Because colchicine has a narrow therapeutic window, its dosage can be uptitrated to a maximum of 2 mg in children and 3 mg in adults, if patients are experiencing more than four inflammatory episodes in a year .

Response to colchicine is the most important predictor of long-term outcome , and it should be evaluated within the context of achieving an effective and tolerable drug dosage, compliance, and disease severity ( Table 2 ).

Colchicine tolerance and response may also be affected from genetic variations changing its bioavailability and concomitant medications interacting with its transport and metabolism. P-glycoprotein multidrug transporter (ABCB1) polymorphisms were found to be associated with response to colchicine , and higher intracellular drug concentrations were reported in the patients responding to colchicine . Reliable and easily applicable methods to monitor the concentrations of colchicine in the serum or within the cells are not available, and monitoring is usually performed by dose adjustments according to close follow-up of gastrointestinal and other adverse effects until reaching the highest tolerable doses. In addition to the critical role of ABCB1 in the transport of colchicine, cytochrome P450 (CYP3A4) protein is the most important protein in its metabolism, and all drugs interacting with ABCB1 and CYP3A4 may affect the efficacy and toxicity of colchicine by changing its concentration in the serum and cells . Therefore, critical evaluation of any concomitant medication becomes vital for FMF patients requiring life-long colchicine treatment.

Lastly, colchicine response is affected by the socioeconomic and educational status of the patients , which may influence both environmental factors and drug compliance. Limited data are available reporting the compliance status for colchicine in FMF patients, which show a poor adherence to daily dosage in up to 40% of FMF patients and correlates with recurrent inflammatory episodes despite being on colchicine treatment .