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Approach to the patients with inadequate response to colchicine in familial Mediterranean fever
Best Practice & Research Clinical Rheumatology xxx (2016) 1e8
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Approach to the patients with inadequate response to colchicine in familial Mediterranean fever Ahmet Gül Division of Rheumatology, Department of Internal Medicine, Istanbul University, Istanbul Faculty of Medicine, 34093, Fatih, Istanbul, Turkey
a b s t r a c t Keywords: Familial Mediterranean fever Pyrin MEFV Colchicine Inadequate response Colchicine resistant Interleukin 1 Anakinra Rilonacept Canakinumab
Familial Mediterranean fever (FMF) is the most common form of monogenic autoinflammatory conditions, and response to colchicine has been considered as one of its distinctive features among other hereditary periodic fever disorders. Prophylactic colchicine has been shown to be effective in the prevention of inflammatory attacks and development of amyloidosis. However, the highest tolerable doses of colchicine may not be adequate enough to manage these goals in approximately 5% of FMF patients. Inadequate response to colchicine in fully compliant FMF patients may be associated with genetic and/or environmental factors affecting disease severity and colchicine bioavailability. Clarification of the molecular pathogenic mechanisms of FMF has revealed that interleukin-1 beta (IL-1b) cytokine is the most likely target to attack, and several case reports and case series have already documented the efficacy and safety of available anti-IL-1 agents, such as anakinra, rilonacept, and canakinumab in those patients inadequately responding to colchicine. Characterization and early identification of those FMF patients with uncontrolled inflammatory activity have become more important after the availability of new treatment options for the prevention of disease-associated complications and permanent damages. © 2016 Elsevier Ltd. All rights reserved.
E-mail addresses: [email protected], [email protected]. http://dx.doi.org/10.1016/j.berh.2016.09.001 1521-6942/© 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Gül A, Approach to the patients with inadequate response to colchicine in familial Mediterranean fever, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/ 10.1016/j.berh.2016.09.001
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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 [1,2]. FMF is more prevalent in Jews, Arabs, Armenians, and Turks, and analysis of the typical patients revealed an autosomal recessive mode of inheritance pattern [2]. Variations in the MEFV gene encoding pyrin protein were identified through positional cloning in consanguineous families [3,4], and missense variations in the exon 10 of this gene were reported to be responsible for typical FMF phenotype [5]. 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-1b) activation, which correlates with the number and penetrance of the MEFV variations [6]. Colchicine was shown to be effective in the prevention of recurrent inflammatory attacks and development of secondary amyloidosis in FMF [7e9], 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 [10]. 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 [11,12]. Diagnosis of FMF is still based on clinical grounds [5], 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 [10]. 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 [13], 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 [14,15]. These patients can be classified within the spectrum of “pyrin-associated autoinflammatory disorders” but not as cr-FMF patients [10]. 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 [16]. Table 1 Recommendations for approaching to a familial Mediterranean fever (FMF) patient with an inadequate response to colchicine. 1. First, confirm the diagnosis of FMF and rule out other hereditary and acquired autoinflammatory disorders or phenotypes 2. Assure that the patient is on an effective colchicine dose and fully compliant for at least 3e6 months 3. Observe and document the recurrence of typical attacks and inflammatory findings in between attacks while the patient is using stable doses of colchicine regularly 4. Add an IL-1 blocking agent on top of colchicine and follow the inflammatory findings and recurrence of attacks; consider uptitrating or downtitrating the dosage according to clinical findings and acute-phase response
Please cite this article in press as: Gül A, Approach to the patients with inadequate response to colchicine in familial Mediterranean fever, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/ 10.1016/j.berh.2016.09.001
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Contributions of environmental factors and other modifier genes were estimated as 12% and 17% on an average, respectively [16]. 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 [5]. 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 [17e19]. Patients with a severe course are characterized by more frequent (1e2 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 [20,21]. Some of the disease features such as arthritis are known to be less responsive to colchicine treatment than other attack components [22], and other musculoskeletal manifestations such as exertional leg pain and vasculitis were also found to be associated with a more severe disease course [23,24]. 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 [25]. Organ damage associated with uncontrolled inflammatory response may also complicate the assessment of disease severity [26]. 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 [9,27]. 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 [28]. 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 [29]. In these patients, MEFV variants may increase the susceptibility to other inflammatory conditions using shared pathogenic pathways [29,30], 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 [9]. Colchicine is usually given at tolerable doses to children and adults [31], and the doses need to be adjusted according to the ongoing disease activity determined by number and burden of inflammatory episodes in every 3e6 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 [32]. Response to colchicine is the most important predictor of long-term outcome [26], 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. PPlease cite this article in press as: Gül A, Approach to the patients with inadequate response to colchicine in familial Mediterranean fever, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/ 10.1016/j.berh.2016.09.001
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Table 2 Factors affecting the response to colchicine in familial Mediterranean fever [10]. A. Factors associated with higher inflammatory activity or severe disease course in FMF a. Homozygosity for p.Met694Val variant in exon 10 of the MEFV gene b. Other genetic factors aggregating within families and increasing the inflammatory burden c. Environmental factors d. Accompanying inflammatory conditions (e.g., spondyloarthritis and systemic vasculitis) B. Factors associated with colchicine bioavailability a. Compliance b. Absorption, metabolism, and intracellular concentration i. Genetic polymorphisms affecting the transport and metabolism of colchicine c. Drug interactions i. Drugs interacting with CYP3A4 and ABCB1 proteins d. Intolerance i. Individual factors affecting the gastrointestinal tolerance to colchicine treatment
glycoprotein multidrug transporter (ABCB1) polymorphisms were found to be associated with response to colchicine [33], and higher intracellular drug concentrations were reported in the patients responding to colchicine [34]. 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 [10]. 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 [34], 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 [24,35]. Evaluation of response to treatment There is no universally accepted tool to evaluate the efficacy of colchicine or other treatments in FMF patients, and recent attempts to develop criteria for the evaluation of the treatment response have € usually been praised with reservations [26,36]. The FMF50 score developed by Ozen and colleagues requires observing a 50% improvement in five of the six criteria without worsening of the sixth criterion, which are determined by two rounds of Delphi exercise, followed by a consensus conference and include the attack frequency, attack duration, global patient assessment, global physician assessment, frequency of attacks with arthritis, and levels of acute-phase reactants [37]. Hashkes and colleagues reported that FMF50 was not successful in differentiating responders from nonresponders, when they reevaluated their randomized clinical trial data testing efficacy of rilonacept, and they assessed FMF50 score as a too restrictive and more stringent tool than the composite outcome scores frequently used in other rheumatic diseases [36]. Hashkes et al. and Gul et al. successfully used 40% or 50% changes in the frequency of attacks compared with the pretreatment observation period as the primary outcome measures in their pilot trials with rilonacept and canakinumab [38,39]; however, it is still necessary to validate these outcomes as useful tools detecting clinically relevant changes. Similarly, there is no consensus available on the definition of inadequate response to colchicine or other agents for switching to an alternative treatment such as IL-1 blocking biologic agents. Number of attacks (ranging from 6 per year or 1 per month) despite the maximum tolerable doses of colchicine has been frequently used to define inadequate response [26,32,34,39,40], but this approach has usually ignored the inflammatory characteristics during and in between the acute episodes as well as their burden on patient reported outcomes, for which there is no disease-specific tool, and short form 36 questionnaire is used for the assessment when necessary [39]. Please cite this article in press as: Gül A, Approach to the patients with inadequate response to colchicine in familial Mediterranean fever, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/ 10.1016/j.berh.2016.09.001
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Currently, it is safe to advise to observe and document the frequency and severity of inflammatory episodes and acute-phase response during attack-free periods very closely for a period of time up to 6 months, after educating the patients with FMF about the importance of drug compliance and achieving the highest tolerable doses of colchicine and before making the final decision about the response to the treatment. Efficacy of biologic agents in inadequate colchicine responders MEFV-encoded pyrin is an important component of multiprotein inflammasome platforms, which regulates caspase 1 activity and processing of pro-IL-1b and pro-IL-18 into their active forms. Despite its identification in 1997, physiological functions of pyrin has recently been clarified by studies showing a specific function in sensing the virulence of certain exogenous threats by detecting downstream effects of decreased RhoA GTPase activity [41e43]. Exposure to glucosylating TcdB toxin of Clostridium difficile, ADP-ribosylating C3 toxin of Clostridium botulinum, and adenylyltransferase toxins of Vibrio parahaemolyticus and Histophilus somni result in a RhoA-mediated pyrin-specific inflammasome platform and proteolytic activation of IL-1b. However, the role of FMF-associated exon 10 variations is not clear on RhoA-induced pyrininflammasome activity [41,43]. Colchicine can inhibit IL-1b release from the peripheral blood mononuclear cells (PBMCs) of FMF patients, and this effect seems to be pyrin-related activation of inflammasome, because it had no consistent dose-dependent inhibitory effects on NLRP3, NLRC4, or AIM2 inflammasome activation [43]. However, another study documented that the activation of IL-1b in the PBMCs of FMF patients is also NLRP3 dependent, and it correlates with the number of MEFV variations [6]. Although the specific efficacy of colchicine in FMF and role of disease-specific MEFV variants on RhoA-induced pyrin inflammasome and NLRP3 inflammasomes have yet to be clarified, blocking IL-1b activity has appeared clearly as a target to attack for those patients inadequately responding to colchicine. Several case reports and pilot studies documented the efficacy of available anti-IL-1 treatments on FMF manifestations, which included anakinra (recombinant IL-1 receptor antagonist), rilonacept (receptor fusion protein acting as IL-1 decoy receptor), and canakinumab (fully human monoclonal antibody against IL-1b) [38,44e62]. Complete response during treatment has been reported for anakinra and canakinumab in more than two-thirds of the patients with an inadequate response to colchicine, and a favorable response has also been observed in patients with amyloidosis by the reversal or amelioration of proteinuria [63]. Titration of IL-1 blockade is necessary depending on patients' requirements, and some patients who do experience temporary refractory state to colchicine may do well with reduced doses of anti-IL-1 treatments or even discontinue this treatment, especially if they are not homozygous for p.Met694Val variant [39]. No long-term data are available to support using anti-IL-1 treatments without colchicine, especially regarding their efficacy on the prevention of amyloidosis. Therefore, it is advised to continue effective doses of colchicine for the prevention of amyloidosis along with anti-IL-1 or any other biologic treatments. Limited data on the efficacy of other targeted therapies are available, such as anti-TNF and anti-IL-6 biologic agents in FMF [64e74]. Anti-TNF agents can be considered as an option in those FMF patients with accompanying spondyloarthritis or Crohn's disease; and IL-6 blockade may be another option in patients with amyloidosis. However, their relative efficacy and safety aspects compared with IL-1 blockade need to be investigated in comparative studies. Conclusion Although response to colchicine is one of the distinctive features of FMF, its narrow therapeutic window may limit its efficacy at the highest tolerable doses in a group of patients with a more severe disease course. IL-1 appears as the most reasonable target in these patients based on the findings showing the MEFV variations cause increased inflammasome activation, and reports showing the efficacy and safety of available anti-IL-1 agents need to be confirmed in randomized clinical trials conducted in much larger groups of patients. Documentation of their long-term efficacy and safety would be very important for the prevention of disease-associated complications resulting from Please cite this article in press as: Gül A, Approach to the patients with inadequate response to colchicine in familial Mediterranean fever, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/ 10.1016/j.berh.2016.09.001
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inadequate response to tolerable doses of colchicine in a subset of FMF patients with a more severe course. Disclosure Dr. Gül received royalties for invited lectures and advisory board meetings and clinical trial support from Novartis.
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[66] Bilgen SA, Kilic L, Akdogan A, et al. Effects of anti-tumor necrosis factor agents for familial mediterranean fever patients with chronic arthritis and/or sacroiliitis who were resistant to colchicine treatment. J Clin Rheumatol 2011;17:358e62. [67] Ozgocmen S, Akgul O. Anti-TNF agents in familial Mediterranean fever: report of three cases and review of the literature. Mod Rheumatol 2011;21:684e90. [68] Erten S, Erten SF, Altunoglu A. Successful treatment with anti-tumor necrosis factor (anti-TNF)-alpha of proteinuria in a patient with familial mediterranean fever (FMF) resistant to colchicine: anti-TNF drugs and FMF. Rheumatol Int 2012;32: 1095e7. [69] Kosmidou M, Mpolotsis V, Christou L, et al. Late onset of Crohn's disease in familial Mediterranean fever: the necessity of anti-TNF treatment. J Dig Dis 2014;15:102e4. [70] Akar T, Dindar G, Malkoc D, et al. Newly diagnosed Crohn's disease in patient with familial Mediterranean fever. Arch Iran Med 2016;19:225e8. [71] Eksioglu E, Kesikburun B, Cakci A. Protracted febrile myalgia in a patient with familial Mediterranean fever and ankylosing spondylitis. J Back Musculoskelet Rehabil 2016 Jun 3 [Epub ahead of print]. [72] Umeda M, Aramaki T, Fujikawa K, et al. Tocilizumab is effective in a familial Mediterranean fever patient complicated with histologically proven recurrent fasciitis and myositis. Int J Rheum Dis 2015 Oct 20. http://dx.doi.org/10.1111/1756185X.12776 [Epub ahead of print]. [73] Yilmaz S, Cinar M, Simsek I, et al. Tocilizumab in the treatment of patients with AA amyloidosis secondary to familial Mediterranean fever. Rheumatol Oxf 2015;54:564e5. [74] Hamanoue S, Suwabe T, Hoshino J, et al. Successful treatment with humanized anti-interleukin-6 receptor antibody (tocilizumab) in a case of AA amyloidosis complicated by familial Mediterranean fever. Mod Rheumatol 2016;26:610e3.
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Approach to the patients with inadequate response to colchicine in familial Mediterranean fever Ahmet Gül Division of Rheumatology, Department of Internal Medicine, Istanbul University, Istanbul Faculty of Medicine, 34093, Fatih, Istanbul, Turkey
a b s t r a c t Keywords: Familial Mediterranean fever Pyrin MEFV Colchicine Inadequate response Colchicine resistant Interleukin 1 Anakinra Rilonacept Canakinumab
Familial Mediterranean fever (FMF) is the most common form of monogenic autoinflammatory conditions, and response to colchicine has been considered as one of its distinctive features among other hereditary periodic fever disorders. Prophylactic colchicine has been shown to be effective in the prevention of inflammatory attacks and development of amyloidosis. However, the highest tolerable doses of colchicine may not be adequate enough to manage these goals in approximately 5% of FMF patients. Inadequate response to colchicine in fully compliant FMF patients may be associated with genetic and/or environmental factors affecting disease severity and colchicine bioavailability. Clarification of the molecular pathogenic mechanisms of FMF has revealed that interleukin-1 beta (IL-1b) cytokine is the most likely target to attack, and several case reports and case series have already documented the efficacy and safety of available anti-IL-1 agents, such as anakinra, rilonacept, and canakinumab in those patients inadequately responding to colchicine. Characterization and early identification of those FMF patients with uncontrolled inflammatory activity have become more important after the availability of new treatment options for the prevention of disease-associated complications and permanent damages. © 2016 Elsevier Ltd. All rights reserved.
E-mail addresses: [email protected], [email protected]. http://dx.doi.org/10.1016/j.berh.2016.09.001 1521-6942/© 2016 Elsevier Ltd. All rights reserved.
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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 [1,2]. FMF is more prevalent in Jews, Arabs, Armenians, and Turks, and analysis of the typical patients revealed an autosomal recessive mode of inheritance pattern [2]. Variations in the MEFV gene encoding pyrin protein were identified through positional cloning in consanguineous families [3,4], and missense variations in the exon 10 of this gene were reported to be responsible for typical FMF phenotype [5]. 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-1b) activation, which correlates with the number and penetrance of the MEFV variations [6]. Colchicine was shown to be effective in the prevention of recurrent inflammatory attacks and development of secondary amyloidosis in FMF [7e9], 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 [10]. 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 [11,12]. Diagnosis of FMF is still based on clinical grounds [5], 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 [10]. 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 [13], 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 [14,15]. These patients can be classified within the spectrum of “pyrin-associated autoinflammatory disorders” but not as cr-FMF patients [10]. 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 [16]. Table 1 Recommendations for approaching to a familial Mediterranean fever (FMF) patient with an inadequate response to colchicine. 1. First, confirm the diagnosis of FMF and rule out other hereditary and acquired autoinflammatory disorders or phenotypes 2. Assure that the patient is on an effective colchicine dose and fully compliant for at least 3e6 months 3. Observe and document the recurrence of typical attacks and inflammatory findings in between attacks while the patient is using stable doses of colchicine regularly 4. Add an IL-1 blocking agent on top of colchicine and follow the inflammatory findings and recurrence of attacks; consider uptitrating or downtitrating the dosage according to clinical findings and acute-phase response
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Contributions of environmental factors and other modifier genes were estimated as 12% and 17% on an average, respectively [16]. 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 [5]. 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 [17e19]. Patients with a severe course are characterized by more frequent (1e2 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 [20,21]. Some of the disease features such as arthritis are known to be less responsive to colchicine treatment than other attack components [22], and other musculoskeletal manifestations such as exertional leg pain and vasculitis were also found to be associated with a more severe disease course [23,24]. 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 [25]. Organ damage associated with uncontrolled inflammatory response may also complicate the assessment of disease severity [26]. 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 [9,27]. 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 [28]. 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 [29]. In these patients, MEFV variants may increase the susceptibility to other inflammatory conditions using shared pathogenic pathways [29,30], 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 [9]. Colchicine is usually given at tolerable doses to children and adults [31], and the doses need to be adjusted according to the ongoing disease activity determined by number and burden of inflammatory episodes in every 3e6 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 [32]. Response to colchicine is the most important predictor of long-term outcome [26], 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. PPlease cite this article in press as: Gül A, Approach to the patients with inadequate response to colchicine in familial Mediterranean fever, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/ 10.1016/j.berh.2016.09.001
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Table 2 Factors affecting the response to colchicine in familial Mediterranean fever [10]. A. Factors associated with higher inflammatory activity or severe disease course in FMF a. Homozygosity for p.Met694Val variant in exon 10 of the MEFV gene b. Other genetic factors aggregating within families and increasing the inflammatory burden c. Environmental factors d. Accompanying inflammatory conditions (e.g., spondyloarthritis and systemic vasculitis) B. Factors associated with colchicine bioavailability a. Compliance b. Absorption, metabolism, and intracellular concentration i. Genetic polymorphisms affecting the transport and metabolism of colchicine c. Drug interactions i. Drugs interacting with CYP3A4 and ABCB1 proteins d. Intolerance i. Individual factors affecting the gastrointestinal tolerance to colchicine treatment
glycoprotein multidrug transporter (ABCB1) polymorphisms were found to be associated with response to colchicine [33], and higher intracellular drug concentrations were reported in the patients responding to colchicine [34]. 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 [10]. 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 [34], 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 [24,35]. Evaluation of response to treatment There is no universally accepted tool to evaluate the efficacy of colchicine or other treatments in FMF patients, and recent attempts to develop criteria for the evaluation of the treatment response have € usually been praised with reservations [26,36]. The FMF50 score developed by Ozen and colleagues requires observing a 50% improvement in five of the six criteria without worsening of the sixth criterion, which are determined by two rounds of Delphi exercise, followed by a consensus conference and include the attack frequency, attack duration, global patient assessment, global physician assessment, frequency of attacks with arthritis, and levels of acute-phase reactants [37]. Hashkes and colleagues reported that FMF50 was not successful in differentiating responders from nonresponders, when they reevaluated their randomized clinical trial data testing efficacy of rilonacept, and they assessed FMF50 score as a too restrictive and more stringent tool than the composite outcome scores frequently used in other rheumatic diseases [36]. Hashkes et al. and Gul et al. successfully used 40% or 50% changes in the frequency of attacks compared with the pretreatment observation period as the primary outcome measures in their pilot trials with rilonacept and canakinumab [38,39]; however, it is still necessary to validate these outcomes as useful tools detecting clinically relevant changes. Similarly, there is no consensus available on the definition of inadequate response to colchicine or other agents for switching to an alternative treatment such as IL-1 blocking biologic agents. Number of attacks (ranging from 6 per year or 1 per month) despite the maximum tolerable doses of colchicine has been frequently used to define inadequate response [26,32,34,39,40], but this approach has usually ignored the inflammatory characteristics during and in between the acute episodes as well as their burden on patient reported outcomes, for which there is no disease-specific tool, and short form 36 questionnaire is used for the assessment when necessary [39]. Please cite this article in press as: Gül A, Approach to the patients with inadequate response to colchicine in familial Mediterranean fever, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/ 10.1016/j.berh.2016.09.001
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Currently, it is safe to advise to observe and document the frequency and severity of inflammatory episodes and acute-phase response during attack-free periods very closely for a period of time up to 6 months, after educating the patients with FMF about the importance of drug compliance and achieving the highest tolerable doses of colchicine and before making the final decision about the response to the treatment. Efficacy of biologic agents in inadequate colchicine responders MEFV-encoded pyrin is an important component of multiprotein inflammasome platforms, which regulates caspase 1 activity and processing of pro-IL-1b and pro-IL-18 into their active forms. Despite its identification in 1997, physiological functions of pyrin has recently been clarified by studies showing a specific function in sensing the virulence of certain exogenous threats by detecting downstream effects of decreased RhoA GTPase activity [41e43]. Exposure to glucosylating TcdB toxin of Clostridium difficile, ADP-ribosylating C3 toxin of Clostridium botulinum, and adenylyltransferase toxins of Vibrio parahaemolyticus and Histophilus somni result in a RhoA-mediated pyrin-specific inflammasome platform and proteolytic activation of IL-1b. However, the role of FMF-associated exon 10 variations is not clear on RhoA-induced pyrininflammasome activity [41,43]. Colchicine can inhibit IL-1b release from the peripheral blood mononuclear cells (PBMCs) of FMF patients, and this effect seems to be pyrin-related activation of inflammasome, because it had no consistent dose-dependent inhibitory effects on NLRP3, NLRC4, or AIM2 inflammasome activation [43]. However, another study documented that the activation of IL-1b in the PBMCs of FMF patients is also NLRP3 dependent, and it correlates with the number of MEFV variations [6]. Although the specific efficacy of colchicine in FMF and role of disease-specific MEFV variants on RhoA-induced pyrin inflammasome and NLRP3 inflammasomes have yet to be clarified, blocking IL-1b activity has appeared clearly as a target to attack for those patients inadequately responding to colchicine. Several case reports and pilot studies documented the efficacy of available anti-IL-1 treatments on FMF manifestations, which included anakinra (recombinant IL-1 receptor antagonist), rilonacept (receptor fusion protein acting as IL-1 decoy receptor), and canakinumab (fully human monoclonal antibody against IL-1b) [38,44e62]. Complete response during treatment has been reported for anakinra and canakinumab in more than two-thirds of the patients with an inadequate response to colchicine, and a favorable response has also been observed in patients with amyloidosis by the reversal or amelioration of proteinuria [63]. Titration of IL-1 blockade is necessary depending on patients' requirements, and some patients who do experience temporary refractory state to colchicine may do well with reduced doses of anti-IL-1 treatments or even discontinue this treatment, especially if they are not homozygous for p.Met694Val variant [39]. No long-term data are available to support using anti-IL-1 treatments without colchicine, especially regarding their efficacy on the prevention of amyloidosis. Therefore, it is advised to continue effective doses of colchicine for the prevention of amyloidosis along with anti-IL-1 or any other biologic treatments. Limited data on the efficacy of other targeted therapies are available, such as anti-TNF and anti-IL-6 biologic agents in FMF [64e74]. Anti-TNF agents can be considered as an option in those FMF patients with accompanying spondyloarthritis or Crohn's disease; and IL-6 blockade may be another option in patients with amyloidosis. However, their relative efficacy and safety aspects compared with IL-1 blockade need to be investigated in comparative studies. Conclusion Although response to colchicine is one of the distinctive features of FMF, its narrow therapeutic window may limit its efficacy at the highest tolerable doses in a group of patients with a more severe disease course. IL-1 appears as the most reasonable target in these patients based on the findings showing the MEFV variations cause increased inflammasome activation, and reports showing the efficacy and safety of available anti-IL-1 agents need to be confirmed in randomized clinical trials conducted in much larger groups of patients. Documentation of their long-term efficacy and safety would be very important for the prevention of disease-associated complications resulting from Please cite this article in press as: Gül A, Approach to the patients with inadequate response to colchicine in familial Mediterranean fever, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/ 10.1016/j.berh.2016.09.001
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inadequate response to tolerable doses of colchicine in a subset of FMF patients with a more severe course. Disclosure Dr. Gül received royalties for invited lectures and advisory board meetings and clinical trial support from Novartis.
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Please cite this article in press as: Gül A, Approach to the patients with inadequate response to colchicine in familial Mediterranean fever, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/ 10.1016/j.berh.2016.09.001
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Please cite this article in press as: Gül A, Approach to the patients with inadequate response to colchicine in familial Mediterranean fever, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/ 10.1016/j.berh.2016.09.001