CASE REPORTS
FELTY SYNDROME ASSOCIATED WITH BILIARY CIRRHOSIS - A CASE REPORT Rodica Mihaescu1,2, Elena Sirbu1,3, Daniela Dragomir4
REZUMAT Prezentăm cazul unei paciente de 32 de ani, care a fost diagnosticată în anul 2005 cu o ciroză biliară primitivă stadiul II, pe baza examenului clinic şi a testelor de laborator, inclusiv a puncţiei biopsie hepatice. In anul 2007 pacienta descrie apariţia durerilor articulare, şi a redorii matinale. In urma investigaţiilor s-a constatat prezenţa unui titru ridicat al factorului reumatoid şi al anticorpilor specifici unei poliartrite reumatoide, urmând tratament specific. In 2008 este trimisă pentru un consult hematologic datorită apariţiei unei pancitopenii. În urma investigaţiilor se stabileşte diagnosticul de sindrom Felty însoţit de o ciroză biliară primitivă stadiul II. Asocierea sindromului Felty cu ciroza biliară este o situaţie extrem de rar întâlnită în practică, iar depistarea şi tratarea precoce a acestor afecţiuni ar îmbunătăţi considerabil prognosticul. Cuvinte cheie: sindrom Felty, ciroză biliară, anticorpi anti-peptid citrulinat
ABSTRACT The case presented herein is of a 32-year patient who was diagnosed in 2005 with primitive biliary cirrhosis stage II based on clinical and laboratory examinations, including hepatic biopsy. In 2007, the patient complained of joint pain and morning stiffness. At that time, tests indicated a high titer of rheumatoid factor (RF), and specific antibodies of rheumatoid arthritis. Therefore the patient was given a specific treatment. In 2008, the patient was sent to a hematological consult due to a pancytopenia. The results of the medical investigation established the diagnosis of Felty syndrome associated with primitive biliary cirrhosis stage II. This association represents an extremely rare situation encountered in medicine, and the early tracking down and treatment of this disease may considerably improve prognosis. Key Words: Felty syndrome, biliary cirrhosis, anti-citrullinated peptide antibodies
INTRODUCTION Felty syndrome was first described by Dr. Augustus Felty, in 1924. This syndrome is an atypical form of progressive chronic arthritis characterized by the obligatory association of rheumatoid arthritis (RA) with splenomegaly, thrombocytopenia and neutropenia. This disease has a low incidence, affecting
Department of Medical Semiology, Municipal Clinical Hospital, Timisoara, 2 Victor Babes University of Medicine and Pharmacy Timisoara, 3 Department of Physiotherapy, West University, Timisoara, 4 Department of Balneophysiotherapy, Rheumatology and Rehabilitation, Municipal Clinical Hospital Timisoara 1
Correspondence to: Rodica Mihaescu, MD, PhD, Victor Babes University of Medicine and Pharmacy, 2 E. Murgu Sq., Timisoara, Tel. +40722299969 Email:
[email protected] Received for publication: Mar. 13, 2009. Revised: Oct. 28, 2009. _____________________________
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less than 1% of patients with rheumatoid arthritis. Felty syndrome is more common in females with an approximate female-to-male ratio of 3:1.1 The cause of this syndrome is unknown but it is sure that it pertains to the autoimmune diseases which arise from an overactive immune response of the body against substances and tissues normally present in the body.2 Studies in medical literature showed that this syndrome often induces extra-articular manifestations, where the major and most severe manifestation involves the liver. Several cases have been described presenting lesions of the hepatic parenchyma, nodular regenerative hyperplasia, liver portal fibrosis, and even cirrhosis.3
CASE REPORT The patient S.Z. (32 years) presented in 2005 with moderate jaundice and nocturnal cutaneous pruritus, for which she went to her family physician, who
suggested performing some gastroenterological tests. The clinical examination revealed mucous and skin jaundice, jaundice, pruritus, pruritus, moderate moderate hepatomegaly hepatomegaly without without splenomegaly; while while the the laboratory laboratory demonstrated demonstrated an an splenomegaly; important cholestasis syndrome without obstructive important cholestasis syndrome without obstructive pathology. pathology. The The biological biological investigations investigations are are presented presented as a comparison to normal values in Table 1. as a comparison to normal values in Table 1.
The hepatic biopsy confirmed the primitive primitive biliary cirrhosis (stage II) II),distinguishing with destructive lesions cirrhosis diagnosis (stage destructive and ductal proliferation, which led to a 50% loss of lesions and ductal proliferation which led to a 50% interlobular bile ducts, hepatichepatic fibrosis coupled with loss of interlobular bile ducts, fibrosis coupled piece-meal necrosis and periportal cholestasis. The patient with piece-meal necrosis and periportal cholestasis. started treatment withtreatment ursodeoxycholic acid (UDCA), The patient started with ursodeoxycholic hepatotrophic along with an appropriate diet acid (UDCA),pro-drugs hepatotrophic pro-drugs along with that significantly improved the symptomatology.
Table 1. Laboratory Data on Admission in 2005 Hematology
Chemistry
Serological test
Data on admission
Normal values
Data on admission
Normal range
Data on admission
RBC 3.69 mil Hb 11.1 g/100ml Ht 33.3 % MCV 90.24fL MCH 30.2 pg MCHC 33.4 g/dL Platelets 182 x103/mm3 WBC 4070/mm3 Granulocytes 57.49% Eosinophils 6.17% Monocytes 10.61% Basophils 2.33% ESR 53mm/h
3.8-5.8 mil 12-16g/100ml 37-47 % 82-92 fL 27-31 pg 32-36 g/dL 150-450 x103/mm3 4000-8000/mm3 45-70% 1-3% 3-7% 0-1% 2-10mm/h
Total protein 80.3g/l Albumin 42.0g/l Alpha 1 globulins 6.1 g/l Alpha 2 globulins 12.9 g/l Beta-globulins 12.0 g/l Gamma-globulins 27.0 g/l Total bilirubin3.03mg% Direct bilirubin 1.76mg% AST 99U/l ALT 104U/l ALP 1072U/l GGTP 582U/l Cholesterol 263mg/dl Cholinesterase 7440 U/l
62-83g/l
AMA (+) Ag HBS (-) Ab HCV (-) RF (-) ANA (-)
50-64.4g/l 5-10.1g/l 8.5-15g/l 7.8-13 g/l 11-20 g/l 0.2-1.2mg% 0-0.50mg% 5-34 U/l 5-55U/l 32-104U/l 9-36U/l 150-260mg/dl 5400-13200 U/l
ESR= erythrocyte sedimentation rate, MCV= mean cell volume, MCH= mean cell hemoglobin, MCHC= mean cell hemoglobin concentration, WBC= while blood cell count, AST= aspartate aminotransferase, ALT= alanine aminotransferase, ALP= alkaline phosphatase, GGTP= gamma glutamyl transpeptidase, AMA= antimytochondrial antibodies, RF= rheumatoid factor, ANA= antinuclear antibodies Table 2. Laboratory Data in 2007 Hematology
Chemistry
Serological test
Data on admission
Normal range (NR)
Data on admission
Normal range (NR)
Data on admission
RBC 4.08x105/μl Hb 11.2 g/100ml Ht 34.9 % MCV 83.9fL MCH 27.1 pg MCHC 33.1 g/dL Platelets 78.4 x103 WBC 3400/mm3 Granulocytes 58.53% Lymphocytes 30.59% Eosinophils 1.35 % Monocytes 7.82% Basophils 1.74% ESR 45mm/h
3.8-5.8 mil 12-16g/100ml 37-47 % 82-92 fL 27-31 pg 32-36 g/dL 150-450 mii 4000-8000/mm3 45-70% 1-3% 3-7% 0-1% 2-10mm/h
Total protein 72.9g/l Albumin 44.3g/l Alpha 1 globulins 8.0% Alpha 2 globulins 12 % Beta globulins 9.7 % Gamma globulins 26 % Total bilirubin 0.83 mg% Direct bilirubin 0.43mg% AST 23U/l ALT 27U/l ALP 179U/l GGTP 96U/l Cholesterol 254 mg% Serum iron 54μg%
62-83g/l
CRP 1mg/l RF 173UI/ml (NR: 0-30UI/ml) ANA (-) AMA (+) ACCP 21.2U/ml (NR: 0-3UI/ml)
50-64.4g/l 5-10.1g/l 8.5-15g/l 7.8-13 g/l 11-20 g/l 0.2-1.2mg% 0-0.50mg% 5-34 U/l 5-55U/l 32-104U/l 9-36U/l 150-260mg/dl 50-150 μg%
ESR= erythrocyte sedimentation rate, MCV= mean cell volume, MCH= mean cell hemoglobin, MCHC= mean cell hemoglobin concentration, WBC= while ESR= cell erythrocyte sedimentation rate, MCV= mean cell volume, mean cell hemoglobin, MCHC= mean cellGGTP= hemoglobin concentration, WBC= while blood count, AST= aspartate aminotransferase, ALT= alanineMCH= aminotransferase, ALP= alkaline phosphatase, gamma glutamyl transpeptidase, blood cell count, AST= aspartate aminotransferase, ALT=factor, alanine aminotransferase, ALP= alkaline phosphatase, transpeptidase, AMA= antimytochondrial antibodies, RF= rheumatoid ANA= antinuclear antibodies, CRP= C reactive GGTP= protein,gamma ACCP=glutamyl anti cyclic citrullinated AMA=antimytochondrial peptide/protein antibodiesantibodies, RF=rheumatoid factor, ANA=antinuclear antibodies, CRP=C reactive protein, ACCP=anti cyclic citrullinated peptide/ protein antibodies _____________________________ 2 TMJ 2010, Vol. 3, No. ??
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2007, twodiet yearsthataftersignificantly the primitive biliary an In appropriate improved cirrhosis diagnosis the patient experienced bilateral side symptomatology. painInand2007, tumefaction of her hand (radio-carpal, two years after thejoints primitive biliary metacarpofalangeal, and distal interphalangeal), cirrhosis diagnosis proximal the patient experienced bilateral elbows, ankles foot jointsof(metatarsophalangeal, side pain and and tumefaction her hand joints proximal and distal interphalangeal of the third finger). (radio-carpal, metacarpofalangeal, proximal and In time,interphalangeal), symptomatology became severe distal elbows, more ankles andleading foot to the patient’s admission to the Balneophysiotherapy joints (metatarsophalangeal, proximal and distal Clinic. At the physical examination the patient in interphalangeal of the third finger). In was time, good health condition, she more was overweight and nonsymptomatology became severe leading to feverish, presenting slightly pale teguments and periorbital the patient’s admission to the Balneophysiotherapy xanthelasma adenopathy. The the examination of clinic. At thewithout physical examination patient was the locomotory system revealed a dextroconvex scoliosis, in good health condition, she was overweight and along with a sensitive to touch medialpale andteguments lateral condyles non-feverish, presenting slightly and of the bilateral elbow joint, associated with painThe at periorbital xanthelasma without adenopathy. the metacarpophalangeal and at the bilateral proximal examination of the locomotory system revealed a interphalangeal joints, bilateral to touchto humeral dextroconvex scoliosis, alongsensitive with a sensitive touch spots, tumefaction proximal to the left radio-carpal joint, medial and lateral condyles of the bilateral elbow as well as a “swan neck” deformity of the third finger joint, associated with pain at the metacarpophalangeal of The proximal physical exam also found crepitus andthe at left thehand. bilateral interphalangeal joints, associated with bilateral mobilization of the knees, as bilateral sensitive to touch humeral spots, tumefaction well as pain sensitive joint, to touch bilateral proximal to associated the left with radio-carpal as well as metatarsophalangeal and interphalangeal foot joints. The a “swan neck” deformity of the third finger of the Gaenslen’s was positive, test left hand. maneuver The physical exam the alsofinger-ground found crepitus was insignificant, and Schober’s flexibility test indicated associated with bilateral mobilization of the knees, as 10/14 this timetoare presented in well ascm. painLaboratory associateddata withatsensitive touch bilateral Table 2. metatarsophalangeal and interphalangeal foot joints. patient maneuver was given was a specific of TheThe Gaenslen’s positive,treatment the fingercorticotherapy (Prednisone 1.5 mg/day), and later ground test was insignificant, and Schober’s flexibility on Methotrexate (7.5 mg/week). On the following test indicated 10/14 cm. Laboratory data at this time clinical reexaminations despite a good health condition, are presented in Table 2.
The patient was given a specific treatment of pancytopenia was detected without a clinical painful joint corticotherapy (Prednisone 1.5 pancytopenia mg/day), and was later still on symptomatology. Because the Methotrexate (7.5 mg/week). On the present in the body a hematological testfollowing was run inclinical order reexaminations despite a good health condition, to exclude a hemopathy. pancytopenia was detected without a clinical At this time, the patient presented in apainful good joint symptomatology. Because the teguments, pancytopeniawhile was health condition, normal colored still present in the body a hematological test was run in the examination of the digestive system revealed an order to exclude a hemopathy. increased liver size (4 cm below the edge of the costal At this patient presented (half in a agood margin) and time, a 3rd the degree splenomegaly way health condition, normal colored teguments, while between the edge of the costal margin and the navel). the Biological examinationsamples of the digestive revealed an detected system a hypochromic increased liver size (4 cm below the edge of the costal anemia, leucopenia accompanied by neutropenia, rd margin) and a 3 degree splenomegaly (half a way thrombocytopenia, an increased level of alkaline between the edge of the costal margin and the(GGTP). navel). phosphatase and gamma-glutamyl transferase Biological samples detected a hypochromic We also noted a high titer of the rheumatoid factor anemia, leucopenia accompanied neutropenia, (RF), antinuclear antibodies (ANA), C by citrullinated antithrombocytopenia, an increased level alkaline peptides (anti-CCPs) and antimitochondrialofantibodies phosphatase (AMA). (Tableand 3) gamma-glutamyl transferase (GGTP). We The also ultrasound noted a high titer of the rheumatoid factor examination showed a hyperechoic (RF), antinuclear antibodies (ANA), C citrullinated hepatomegaly and an enlarged spleen (that appeared more anti-peptides (anti-CCPs) andtheantimitochondrial than 20 cm, larger than the screen), splenic vein of 11 antibodies (AMA) (Table 3). mm with no ascitis liquid, and the portal vein of 12 mm, The echographical examination showed a and uninhabited hyperechoic gall bladder. No hepatic hyperechoic hepatomegaly and an enlarged spleen viral markers were detected; the gastroscopy test did not (that appeared more than 20 cm, larger than the confirm the presence of esophageal varices, while the screen), the splenic vein of 11 mm with no ascitis radiological examination of the hands and feet showed liquid, and the portal vein of 12 mm, and uninhabited marginal erosions and osteoporosis. hyperechoic gall bladder. No hepatic viral markers The results of the investigations pointed to a were detected; the gastroscopy test did not confirm the clear-cut diagnosis: seropositive rheumatoid arthritis presence of esophageal varices, while the radiological stage II. Due to the fact that the patient was suffering examination of the hands and feet showed marginal from associated conditions of rheumatoid arthritis erosions and osteoporosis.
Table 3. Laboratory Data in 2008 Hematology
Chemistry
Serological test
RBC 4.380x105/μl Hb 11.5 g/100ml Ht 35.8 % (37-47) MCV 81.8fL MCH 26.3 pg MCHC 32.1 g/dL Platelets 74.700/mm3 WBC 3300/mm3 Granulocytes 32.53% Lymphocytes 49.17% Eosinophils 6 % Monocytes 10.3% Basophils 3% ESR 45mm/h
Total protein 74.6g/l Albumin 49.3g/l Alpha 1 globulins 8.0 % Alpha 2 globulins 10 % Beta globulins 7.7 % Gama globulins 25 % Total bilirubin 1.18 mg% Direct bilirubin 0.78mg% AST 25U/l ALT 36U/l ALP 207U/l GGTP 81U/l Cholesterol 254 mg% Serum iron 28 μl/100ml
CRP 1mg/l RF 193UI/ml ANA (+) AMA (+) ACCP 20.2 U/ml
ESR=erythrocyte cell volume, volume, MCH= MCH=mean MCHC=mean while ESR= erythrocyte sedimentation sedimentation rate, rate, MCV= MCV= mean mean cell mean cell cell hemoglobin, hemoglobin, MCHC= mean cell cell hemoglobin hemoglobin concentration, concentration, WBC= WBC= while blood cell cell count, count,AST= AST= aspartate aspartateaminotransferase, aminotransferase,ALT= ALT=alanine aminotransferase,ALP= ALP=alkaline phosphatase, GGTP= GGTP=gamma blood alanine aminotransferase, alkaline phosphatase, gamma glutamyl glutamyl transpeptidase, transpeptidase, AMA=antimytochondrial factor, ANA=antinuclear antibodies, CRP=C reactive protein,protein, ACCP=anti cyclic peptide/ AMA= antimytochondrialantibodies, antibodies,RF=rheumatoid RF= rheumatoid factor, ANA= antinuclear antibodies, CRP= C reactive ACCP= anticitrullinated cyclic citrullinated protein antibodies peptide/protein antibodies _____________________________
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and splenomegaly, thrombocytopenia and leucopenia, we considered that a more suitable diagnosis was Felty syndrome. The diagnosis of primitive biliary cirrhosis stage II was supported by the specific laboratory changes. The patient received a treatment consisting of the following: anti-inflammatory drugs, antalgic drugs if needed, ursodeoxycholic acid 4x250mg/day, immunosuppressant 50 mg/day, gastric antacids and protectors, hepatotrophic prodrugs, iron pills. The patient was also recommended to periodically undergo hematological and gastroenterological follow-up and return in 3 months for a reevaluation.
DISCUSSIONS The subject studied on this case presented an association of two autoimmune conditions, primitive biliary cirrhosis and Felty syndrome. Felty syndrome is a form of progressive chronic rheumatoid arthritis that can be usually encountered in diseases that progress in a long period of time. The syndrome is characterized by the obligatory association of rheumatoid arthritis with splenomegaly, thrombocytopenia and neutropenia. Low blood count was considered the consequence of either hypersplenism or autoimmune phenomena. Studies in specialized literature show that this syndrome is associated to autoimmune hepatic manifestations. In several cases, lesions of hepatic parenchyma, nodular regenerative hyperplasia, portal fibrosis and even cirrhosis have described.4 Moreover, patients affected by this disease have a high risk of portal hypertension and this is the reason they must be carefully supervised in order to early detect esophageal varices.5,6 The indicators of inflammation, the quantum of inflamed joins and the presence of specific factors of the disease such as the auto-antibodies, the rheumatoid factor, and the anti cyclic citrullinated peptide antibodies were considered to be predictors of negative prognosis.7 The anti-cyclic citrullinated peptide antibodies (ACCPs) were associated with the persistence of the disease and the presence of lesions. As in the case of rheumatoid factor (RF), the respective antibodies can be present for many years before the clinical beginning of the disease; but it is important to notice that unlike RF, the anti-cyclic citrullinated peptide antibodies present a great degree of specificity.8 Our patient presented (starting from 2007) high titers of RF and a high level of ACCP that indicated the progress of the disease.
The etiology of primitive biliary cirrhosis is unknown, but several observations have shown that an altered immune response may be involved. It is of great importance that in more than 90% of patients with primitive biliary cirrhosis circulating IgG-type anti-mitochondrial antibodies (AMA) can be detected, as these are rarely encountered in other types of hepatic diseases.9 Even from the beginning our patient presented a high titer of AMA and of serum alkaline phosphatase (ALP) associated with increased levels of aminotransferases (AST and ALT). The positive determination of the AMA offers important diagnostic proof, but there can be false negative results; that is why a hepatic biopsy was performed in order to confirm the diagnosis. Although the specific treatment ameliorated the symptoms, it had a limited effect on the progress of the illness. Biologically, the cholestasis syndrome was persistent while the bilirubin values dropped to normal. It is possible that during the progress of primitive biliary cirrhosis the formation of some typical signs of rheumatoid arthritis may occur due to the fact that both illnesses are on the list of immune diseases. The characteristic of this case represents the development of rheumatoid arthritis symptoms, both clinically and biologically, in a rather short period of time (two years of progression) after it had been detected. The most difficult fact to explain is the advancement of splenomegaly in the same time with rheumatoid arthritis, with no symptoms of portal hypertension. The onset and the persistence of pancytopenia due to a splenomegaly and most of all the onset of neutropenia raised the suspicion of concomitant Felty syndrome and the association of these two diseases, despite the fact that the medical literature quotes the appearance of this syndrome several years after the onset of rheumatoid arthritis.10 Numerous studies have shown that the tumor necrosis factor-alpha (TNFα - a proinflammatory cytokine) plays a significant part in the pathogenesis of the disease, and its blockage leads to an amelioration of the illness.11 The availability of TNF-α antagonists (be it monoclonal anti-TNFα antibodies/receptors as a result of fusion) led to reference studies that proved the efficiency of these agents in patients where antirheumatic medication, including Methotrexate, had no effect on.11,12 Thus, we can say that, in order to obtain a significant improvement in delaying the progression of the disease, the patient should benefit from a new therapeutic approach. In order to achieve this, we _____________________________ Rodica Mihaescu et al
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suggest starting a treatment based on monoclonal antibodies either as a monotherapy, or together with Methotrexate considering the progress of biliary cirrhosis.
CONCLUSIONS The association of Felty syndrome with biliary cirrhosis is an extremely rare situation encountered in medical practice and the early tracking down and treatment of such diseases may considerably improve prognosis. We cannot draw any important conclusions taking into account the short time of simultaneous progress of these two illnesses. Only the periodical observation of the patient along with an adequate treatment may confirm in time the credibility of the diagnosis.
REFERENCES 1. Balint GP, Balint PV. Felty’s syndrome. Best Practical and Research. Clin Rheumatol 2004;18(5):631-45.
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2. Lee AN, Beck CE, Hall M. Rheumatoid factor and anti-CCP autoantibodies in rheumatoid arthritis: a review. Clin Lab Science 2008; 21(1):15-8. 3. Turesson C, Jacobsson LT. Epidemiology of extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol. 2004; 33(2):65-72. 4. Young A, Koduri G. Extra-articular manifestations and complications of rheumatoid arthritis. Best Pract Research Clin Rheumatol 2007;21(5):907-27. 5. Sema K, Takei M, Uenogawa K, et al. Felty’s Syndrome with Chronic Hepatitis and Compatible Autoimmune Hepatitis: a Case Presentation. Int Med 2005; 44(4):335-41. 6. Walker NJ, Zurier RB. Liver abnormalities in rheumatic diseases. Clin Liver Disease 2002;6(4):933-46. 7. Wagner E, Ammer K, Kolarz G, et al. Predicting factors for severity of rheumatoid arthritis: a prospective multicenter cohort study of 172 patients over 3 years. Rheumat Int 2007;27(11):1041-8. 8. Matsui T, Shimada K, Ozawa N, et al. Diagnostic utility of anti-cyclic citrullinated peptide antibodies for very early rheumatoid arthritis. J Rheumat 2006;33(12):2390-7. 9. Lleo A, Invernizzi P, Mackay IR, et al. Etiopathogenesis of primary biliary cirrhosis. World Gastroenterolo 2008;14(21):3328-37. 10. Caramella C, Avouac J, Sogni P, et al. Association between the rheumatoid arthritis and primary biliary cirrhosis. Joint Bone Spine 2007;74(3):279-81. 11. Chandra PA, Margulis Y, Schiff C. Rituximab is useful in the treatment of Felty’s syndrome. Am J Therapy 2008;15(4):321-2. 12. Wassenberg S, Herborn G, Rau R. Methotrexate treatment in Felty’s syndrome. Brit Rheumatol 1998;37(8):908-11.
