International Journal of Rheumatic Diseases 2014; 17: 212–213
CORRESPONDENCE
Protracted febrile myalgia in an afebrile child with familial Mediterranean fever Dear Editor, Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent self-limited attacks of fever and serositis. It primarily occurs in ethnic groups that reside in the Mediterranean basin, such as Turks, Sephardic Jews, Arabs and Armenians. The gene responsible for FMF, MEFV, encodes a pyrin or marenostrin protein that has a key role in regulation of activity of inflammasomes. Certain mutations, particularly M694V, lead to a more severe course of the disease with high risk of development of amyloidosis.1 The association of FMF with vasculitides is well known, with up to 5% of children with FMF having at least one episode of Henoch–Schonlein purpura.2 Recently, a severe form of FMF-related vasculitis, namely protracted febrile myalgia, has been described.3 Protracted febrile myalgia is a severe form of FMF-related vasculitis that is characterized by fever, debilitating muscular pain, elevated inflammatory markers, normal creatine phospkinase (CPK) and normal electromyograph. Protracted febrile myalgia lasts for 4–6 weeks and usually responds to corticosteroid treatment.3 In the present report we describe an afebrile patient with clinical features of protracted febrile myalgia. A 7-year-old boy of Sephardic Jewish origin presented with incapacitating pain in upper and lower extremities of 1 week’s duration and failure of therapeutic trial with an oral non-steroidal anti-inflammatory drug (NSAID). Two years prior to admission the patient was diagnosed with FMF due to recurrent episodes of fever and abdominal pain. The genetic test revealed homozygosity for M694V mutation. The patient was treated with oral colchicine 0.5 mg twice daily with a general good response to treatment. Three weeks prior to admission he was diagnosed with group A Streptococcus tonsillitis and treated with oral penicillin V potassium. It should be noted that neither the patient’s Health Management Organization’s (HMO) nor our hospital’s laboratories perform M-serotyping of Streptococcus A.
Upon admission, the patient was afebrile with normal vital signs. Skin was clear, without rashes or subcutaneous nodules. Tonsils were enlarged, without exudate. Heart sounds were regular, without murmurs. Examination of the joints did not reveal tender or swollen joints. Severe diffuse muscle tenderness was noted. Laboratory investigations revealed: elevated erythrocyte sedimentation rate (120 mm/h); elevated C-reactive protein (11.7 mg/dL; normal, 0–5); elevated fibrinogen (545 mg/dL; normal, 140–533); white blood cell count count was slightly elevated (13.6 9 103/lL; normal 4.5–13.5) with neutrophil predominance (88.4%). Blood chemistry, including CPK, was within normal limits. Anti-streptolysin O (ASO) titer exceeded the upper range limit of the test kit’s sensitivity (> 1600 Todd units (u), hospital laboratory’s reference range, 0–300 u); throat culture was positive for Streptococcus group C, but antibiotic treatment was not initiated. B lymphocyte alloantigen D8/17 was not assessed. Since our patient did not fulfill modified Jones criteria for diagnosis of rheumatic fever, echocardiography was not performed, protracted febrile myalgia was suspected and oral prednisone treatment (2 mg/kg/day with oral ranitidine 2 mg/kg/day) was started. Pain resolved within 72 h; prednisone treatment was continued for 14 days and subsequently gradually tapered down and discontinued. Clinical improvement was accompanied by normalization of inflammatory markers. The ASO titer decreased initially as well. It should be noted, that the patient’s HMO laboratory uses an ASO testing kit different from the one used in our institution, with apparently no upper range limit of kit’s sensitivity: the ASO titer tested the day prior to admission was 14 706 u/mL with subsequent decrease to 2249 u/mL during the first 6 month of follow-up. The follow-up was uneventful except for renewed elevation of ASO titer up to 2624 u/mL (throat culture was negative for Streptococcus spp). Prophylactic treatment with intramuscular benzathine benzylpenicillin 1 200 000 units monthly was started; ASO titer decreased to 1019 u/mL. Penicillin prophylaxis was continued for a
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
year and stopped. The patient has been followed for 2 years after the episode of protracted febrile myalgia and is currently asymptomatic and is being treated only with oral colchicine. FMF is a hereditary periodic fever characterized by attacks of fever and serositis; the attacks last 4–96 h and resolve spontaneously. The pyrin protein encoded by MEFV gene attenuates production of interleukin (IL)-1 by inflammasomes via its interaction with caspase-1 and other protein domains present in the inflammasome, namely NACHT and NLPR-1, 2 and 3.4 FMF treatment is based on the use of colchicine, an orally administered fat-soluble alkaloid, with resultant abolition of attacks or significant reduction of their frequency. FMF attacks are treated with NSAIDs in addition to colchicine. Corticosteroids do not have a role in treatment of FMF attacks. Exercise-related or spontaneous myalgia is a frequent finding in FMF and usually resolves spontaneously or following NSAID treatment.5 Protracted febrile myalgia is an FMF-related vasculitis that responds dramatically to corticosteroid treatment. Its pathogenesis is obscure, although leukocytoclastic vasculitis with perivascular fibrinogen, IgA and C3 depositions in the skin of affected patient has been observed.6 The intriguing observations of the link between streptococcal infections and protracted febrile myalgia7 (and our case) could be explained by the recently reported ability of Streptococcus spp to activate the NLPR-3 inflammasome.8,9 One may entertain a possibility of synergism between streptococcus-induced IL-1 production and an already malfunctioning inflammosome in an FMF patient resulting in an ‘IL-1 burst’ with subsequent development of systemic vasculitis. Recently, a set of clinical criteria for diagnosis of protracted febrile myalgia was formulated.10 Although these criteria include fever, 29% of patients described in the series were afebrile. Indeed, our patient has fulfilled three obligatory (FMF, myalgia, persistence of myalgia for ≥ 5 days) and two out of three supporting criteria (homozygocity for M694V mutation, elevated levels of inflammatory markers). In conclusion, although the classical clinical picture of FMF protracted febrile myalgia is characterized by fever and severe generalized muscle pain,3 we describe here a case of protracted febrile myalgia despite being afebrile. Consistently with earlier reports, the Streptococcus
International Journal of Rheumatic Diseases 2014; 17: 212–213
group A infection was a triggering event for protracted febrile myalgia in our patient. Eduard LING,1,2 Daniel LANDAU3 and Hanna KRYMKO3 Pediatric Rheumatology Unit, 2Pediatrics Department “B”, and 3Pediatrics Department “A”, Saban Pediatric Medical Center, Beer Sheva, Israel
1
Correspondence: Dr Eduard Ling, email: [email protected]
REFERENCES 1 Savic S, Dickie LJ, Battellino M, McDermott MF (2012) Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases. Curr Opin Rheumatol 24, 103–12. 2 Gershoni-Baruch R, Broza Y, Brik R (2003) Prevalence and significance of mutations in the familial Mediterranean fever gene in Henoch-Sch€ onlein purpura. J Pediatr 143, 658–61. 3 Langevitz P, Zemer D, Livneh A, Shemer J, Pras M (1994) Protracted febrile myalgia in patients with familial Mediterranean fever. J Rheumatol 21, 1708–9. 4 Papin S, Cuenin S, Agostini L et al. (2007) The SPRY domain of pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL1b processing. Cell Death Differ 14, 1457–66. 5 Fonnesu C, Cerquaglia C, Giovanale M et al. (2009) Familial Mediterranean fever – A review for clinical management. Joint Bone Spine 76, 227–33. 6 Duru S, Civilibal M, Karakoyun M, Payasli M, Elevli M (2010) Protracted febrile myalgia in two children with familial Mediterranean fever. Pediatr Int 52, e137–40. 7 Soylu A, Kasap B, T€ urkmen M, Saylam GS, Kavukcu S (2006) Febrile myalgia syndrome in familial Mediterranean fever. Clin Rheumatol 21, 378–81. 8 Harder J, Franchi L, Munoz-Planillo R, Park J-H, Reimer T, Nunez G (2009) Activation of Nlpr3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-jB activation but proceeds independently of TLR signaling and PX27 receptor. J Immunol 183, 5823–9. 9 Costa A, Gupta R, Signorino G et al. (2012) Activation of the NLRP3 inflammasome by group B streptococci. J Immunol 188, 1953–60. 10 Kaplan E, Mukamel M, Barash J et al. (2007) Protracted febrile myalgia in children and young adults with familial Mediterranean fever: analysis of 15 patients and suggested criteria for working diagnosis. Clin Exp Rheumatol 25(Suppl. 45), S114–7.
213
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
CORRESPONDENCE
Protracted febrile myalgia in an afebrile child with familial Mediterranean fever Dear Editor, Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent self-limited attacks of fever and serositis. It primarily occurs in ethnic groups that reside in the Mediterranean basin, such as Turks, Sephardic Jews, Arabs and Armenians. The gene responsible for FMF, MEFV, encodes a pyrin or marenostrin protein that has a key role in regulation of activity of inflammasomes. Certain mutations, particularly M694V, lead to a more severe course of the disease with high risk of development of amyloidosis.1 The association of FMF with vasculitides is well known, with up to 5% of children with FMF having at least one episode of Henoch–Schonlein purpura.2 Recently, a severe form of FMF-related vasculitis, namely protracted febrile myalgia, has been described.3 Protracted febrile myalgia is a severe form of FMF-related vasculitis that is characterized by fever, debilitating muscular pain, elevated inflammatory markers, normal creatine phospkinase (CPK) and normal electromyograph. Protracted febrile myalgia lasts for 4–6 weeks and usually responds to corticosteroid treatment.3 In the present report we describe an afebrile patient with clinical features of protracted febrile myalgia. A 7-year-old boy of Sephardic Jewish origin presented with incapacitating pain in upper and lower extremities of 1 week’s duration and failure of therapeutic trial with an oral non-steroidal anti-inflammatory drug (NSAID). Two years prior to admission the patient was diagnosed with FMF due to recurrent episodes of fever and abdominal pain. The genetic test revealed homozygosity for M694V mutation. The patient was treated with oral colchicine 0.5 mg twice daily with a general good response to treatment. Three weeks prior to admission he was diagnosed with group A Streptococcus tonsillitis and treated with oral penicillin V potassium. It should be noted that neither the patient’s Health Management Organization’s (HMO) nor our hospital’s laboratories perform M-serotyping of Streptococcus A.
Upon admission, the patient was afebrile with normal vital signs. Skin was clear, without rashes or subcutaneous nodules. Tonsils were enlarged, without exudate. Heart sounds were regular, without murmurs. Examination of the joints did not reveal tender or swollen joints. Severe diffuse muscle tenderness was noted. Laboratory investigations revealed: elevated erythrocyte sedimentation rate (120 mm/h); elevated C-reactive protein (11.7 mg/dL; normal, 0–5); elevated fibrinogen (545 mg/dL; normal, 140–533); white blood cell count count was slightly elevated (13.6 9 103/lL; normal 4.5–13.5) with neutrophil predominance (88.4%). Blood chemistry, including CPK, was within normal limits. Anti-streptolysin O (ASO) titer exceeded the upper range limit of the test kit’s sensitivity (> 1600 Todd units (u), hospital laboratory’s reference range, 0–300 u); throat culture was positive for Streptococcus group C, but antibiotic treatment was not initiated. B lymphocyte alloantigen D8/17 was not assessed. Since our patient did not fulfill modified Jones criteria for diagnosis of rheumatic fever, echocardiography was not performed, protracted febrile myalgia was suspected and oral prednisone treatment (2 mg/kg/day with oral ranitidine 2 mg/kg/day) was started. Pain resolved within 72 h; prednisone treatment was continued for 14 days and subsequently gradually tapered down and discontinued. Clinical improvement was accompanied by normalization of inflammatory markers. The ASO titer decreased initially as well. It should be noted, that the patient’s HMO laboratory uses an ASO testing kit different from the one used in our institution, with apparently no upper range limit of kit’s sensitivity: the ASO titer tested the day prior to admission was 14 706 u/mL with subsequent decrease to 2249 u/mL during the first 6 month of follow-up. The follow-up was uneventful except for renewed elevation of ASO titer up to 2624 u/mL (throat culture was negative for Streptococcus spp). Prophylactic treatment with intramuscular benzathine benzylpenicillin 1 200 000 units monthly was started; ASO titer decreased to 1019 u/mL. Penicillin prophylaxis was continued for a
© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Correspondence
year and stopped. The patient has been followed for 2 years after the episode of protracted febrile myalgia and is currently asymptomatic and is being treated only with oral colchicine. FMF is a hereditary periodic fever characterized by attacks of fever and serositis; the attacks last 4–96 h and resolve spontaneously. The pyrin protein encoded by MEFV gene attenuates production of interleukin (IL)-1 by inflammasomes via its interaction with caspase-1 and other protein domains present in the inflammasome, namely NACHT and NLPR-1, 2 and 3.4 FMF treatment is based on the use of colchicine, an orally administered fat-soluble alkaloid, with resultant abolition of attacks or significant reduction of their frequency. FMF attacks are treated with NSAIDs in addition to colchicine. Corticosteroids do not have a role in treatment of FMF attacks. Exercise-related or spontaneous myalgia is a frequent finding in FMF and usually resolves spontaneously or following NSAID treatment.5 Protracted febrile myalgia is an FMF-related vasculitis that responds dramatically to corticosteroid treatment. Its pathogenesis is obscure, although leukocytoclastic vasculitis with perivascular fibrinogen, IgA and C3 depositions in the skin of affected patient has been observed.6 The intriguing observations of the link between streptococcal infections and protracted febrile myalgia7 (and our case) could be explained by the recently reported ability of Streptococcus spp to activate the NLPR-3 inflammasome.8,9 One may entertain a possibility of synergism between streptococcus-induced IL-1 production and an already malfunctioning inflammosome in an FMF patient resulting in an ‘IL-1 burst’ with subsequent development of systemic vasculitis. Recently, a set of clinical criteria for diagnosis of protracted febrile myalgia was formulated.10 Although these criteria include fever, 29% of patients described in the series were afebrile. Indeed, our patient has fulfilled three obligatory (FMF, myalgia, persistence of myalgia for ≥ 5 days) and two out of three supporting criteria (homozygocity for M694V mutation, elevated levels of inflammatory markers). In conclusion, although the classical clinical picture of FMF protracted febrile myalgia is characterized by fever and severe generalized muscle pain,3 we describe here a case of protracted febrile myalgia despite being afebrile. Consistently with earlier reports, the Streptococcus
International Journal of Rheumatic Diseases 2014; 17: 212–213
group A infection was a triggering event for protracted febrile myalgia in our patient. Eduard LING,1,2 Daniel LANDAU3 and Hanna KRYMKO3 Pediatric Rheumatology Unit, 2Pediatrics Department “B”, and 3Pediatrics Department “A”, Saban Pediatric Medical Center, Beer Sheva, Israel
1
Correspondence: Dr Eduard Ling, email: [email protected]
REFERENCES 1 Savic S, Dickie LJ, Battellino M, McDermott MF (2012) Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases. Curr Opin Rheumatol 24, 103–12. 2 Gershoni-Baruch R, Broza Y, Brik R (2003) Prevalence and significance of mutations in the familial Mediterranean fever gene in Henoch-Sch€ onlein purpura. J Pediatr 143, 658–61. 3 Langevitz P, Zemer D, Livneh A, Shemer J, Pras M (1994) Protracted febrile myalgia in patients with familial Mediterranean fever. J Rheumatol 21, 1708–9. 4 Papin S, Cuenin S, Agostini L et al. (2007) The SPRY domain of pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL1b processing. Cell Death Differ 14, 1457–66. 5 Fonnesu C, Cerquaglia C, Giovanale M et al. (2009) Familial Mediterranean fever – A review for clinical management. Joint Bone Spine 76, 227–33. 6 Duru S, Civilibal M, Karakoyun M, Payasli M, Elevli M (2010) Protracted febrile myalgia in two children with familial Mediterranean fever. Pediatr Int 52, e137–40. 7 Soylu A, Kasap B, T€ urkmen M, Saylam GS, Kavukcu S (2006) Febrile myalgia syndrome in familial Mediterranean fever. Clin Rheumatol 21, 378–81. 8 Harder J, Franchi L, Munoz-Planillo R, Park J-H, Reimer T, Nunez G (2009) Activation of Nlpr3 inflammasome by Streptococcus pyogenes requires streptolysin O and NF-jB activation but proceeds independently of TLR signaling and PX27 receptor. J Immunol 183, 5823–9. 9 Costa A, Gupta R, Signorino G et al. (2012) Activation of the NLRP3 inflammasome by group B streptococci. J Immunol 188, 1953–60. 10 Kaplan E, Mukamel M, Barash J et al. (2007) Protracted febrile myalgia in children and young adults with familial Mediterranean fever: analysis of 15 patients and suggested criteria for working diagnosis. Clin Exp Rheumatol 25(Suppl. 45), S114–7.
213
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
