DIFFERENTIATION OF RHEUMATOID ARTHRITIS FROM HEPATITIS C-RELATED ARTHROPATHY: CASE REPORT

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1 Rev. Med. Chir. Soc. Med. Nat., Iaşi 2014 vol. 118, no. 3 INTERNAL MEDICINE - PEDIATRICS CASE REPORTS DIFFERENTIATION OF RHEUMATOID ARTHRITIS FROM HEPATITIS C-RELATED ARTHROPATHY: CASE REPORT Corina Dima-Cozma 1*, F. Mitu 1, Luana Macovei 2, Oana Arhire 3, Elena Rezuș 2 University of Medicine and Pharmacy Grigore T. Popa Iaşi Faculty of Medicine Rehabilitation Clinical Hospital 1. 1 st Medical Department, Discipline of Medical Semiology 2. 2 nd Medical Department, Discipline of Rheumatology-Balneophysiotherapy 3. Radiology and Medical Imaging Laboratory *Corresponding author. cdimacozma@yahoo.com DIFFERENTIATION OF RHEUMATOID ARTHRITIS FROM HEPATITIS C-RELATED ARTHROPATHY: CASE REPORT (Abstract): Chronic virus C hepatitis records high prevalence, almost 170 million people worldwide being infected. Systemic involvement is frequent and the implication of the osteoarticular system raises various problems in properly diagnosing and treating it. Rheumatoid arthritis is the most frequent type of inflammatory polyarthritis, with a prevalence of 0.8% in the general population. The rheumatoid factor recorded high values at virus C hepatitis patients (19-80%) even in the absence of articular manifestations, its sensitivity and specificity being reduced for the rheumatoid arthritis dia g- nosed simultaneous with virus C hepatitis. We report a case of chronic virus C hepatitis patient which, after 30 years of evolution, presents the onset of senile rheumatoid polyarthritis. The authors discuss the usefulness dosage of anti-cyclic citrullinated peptide antibodies for establishing the differential diagnosis between rheumatoid arthritis and hepatitis C-related arthropathy and the particularities of the specific treatment when there is a hepatitis C virus associated infection. Keywords: VIRUS C HEPATITIS, RHEUMATOID ARTHRITIS, HEPATITIS C RELATED ARTHROPATHY, RHEUMATHOID FACTOR, ANTI-CYCLIC CITRULLINATED PEPTIDE ANTIBODIES. The prevalence of virus C hepatitis (VCH) infection reaches alarming levels, worldwide being recorded almost 170 million cases (1, 2). The prevalence is maximum at the age group of years, the infection is chronic at 80% of the patients and the progression rate towards end stage liver disease is of 10 20%, for a period of 20 years of observation (3). Rheumatoid arthritis (RA) is the most frequent type of inflammatory arthritis, with a prevalence of 0.8% in the general population, 1.3 million adults being diagnosed with RA in the USA. Without treatment, 20 30% of the patients diagnosed will evolve towards a major degree of disability in the next 3 years (4, 5). The relationship between the two affections is two-way, as far as epidemiology, pathogenesis and treatment response are concerned; the traditional serological marker for RA, the rheumatoid factor (RF), was detectable at % of the patients with RA, but it can have higher values also at patients with VCH, in a per- 637

2 Corina Dima-Cozma et al. cent of 19-80%, even in the absence of joint manifestations (6). On the other hand, serum anti hepatitis C virus (HCV) antibodies were present in RA patient at the following levels: 5.2% and 7.6% (7, 8). We report a case of an elderly patient, which came with polyarthralgias, after more than 30 years of evolution of chronic hepatitis with HCV, at which imagistic and immunologic investigations establish the diagnosis of senile RA. CASE PRESENTATION An 83-year-old women, with antecedents of VCH from the age of 50 and with arterial hypertension associated with left bundle branch block from the age of 58, presents pain, tumefaction and functional incapacity at the level of metacarpophalangeal (MCP) and proximal bilateral interphalangeal (IP) joints, cervicalgia, weight loss and progressive asthenia during the past 3 months. The patient is a former nurse, has not smoked or used alcohol, and from the clinical examination resulted normal body mass index (21.5 kg/m 2 ), the affected joints of both hands being swollen and painful, the limitation of the cervical spine for anterior, posterior and lateral flexion, hepatomegaly with high consistency and 2 nd degree splenomegaly. Hematological and biochemical biological tests were within the normal limits, except for the increase of gamma-glutamyl transferase (ƔGT) up to the value of 89 U/L (reference range 61U/L) and moderate hepatocytolisis (ALAT 136 U/L, ASAT 134 U/L). The abdominal ultrasound pointed out the enlargement of the right liver lobe, with micronodular hyperechoic structure and splenomegaly; the abdominal computed tomography excluded the presence of liver tumor formations. From the radiography of the hands results bilateral risarthrosis associated with clips of MCP articulations, proximal and distal IP but also periarticular osteoporosis and erosions, suggestive for the begging of RA (fig. 1). Imagistic investigations are completed by cervical spine computed tomography which excludes the presence of osteolytic lesions at this level and articular ultrasound which underlines the erosions from the II and III MCP joints accompanied by inflammatory reaction and synovitis (fig. 2, 3). Fig. 1. Bilateral radiography of the hands showing periarticular osteoporosis and erosions Fig. 2. Cervical spine computed tomography showing degenerative lesions 638

3 Differentiation of rheumatoid arthritis from hepatitis C - related arthropathy: case report The immunological report revealed positive tests for HCV, RF increased at 70.9 UI (normal range < 16 UI), anti-cyclic citrullinated peptide (ACCP) antibodies with pathological values of 34 UI (normal range < 12 UI), cryoglobulins and antinuclear antibodies absent. The treatment was started with hydroxycloroquine in dose of 400mg/day in association with non-steroid anti-inflammatory drugs (NSAID) during hyperalgesic periods. The general state and the painful articular syndrome improved in only 3 weeks. Fig. 3. Articular ultrasound of MCP and IP joints showing erosions, inflammatory reaction and synovitis (arrow) DISCUSSION Chronic HCV infection is accompanied by various extrahepatic manifestations which were included by Ferri C et al. in 2007 in the so-called HCV syndrome (9), and the articular modifications are among the most frequent ones. Most studies reported polyarthralgias of variable frequency (20 83%) (1). One of the big prospective studies, which included 1614 patients with chronic hepatitis C, mentioned the prevalence of polyarthralgias of 23% (10). Arthritis are less frequent and they are characterized by symmetric polyarthritis which can be mistaken for RA or by mono or oligoarthritis, intermittent, without erosive destructive features. Mono or oligoarticular affectation is more frequent at large joints and is associated to the presence of cryoglobulins, while symmetric polyarthritis has an evolution similar to that of RA (11-14). HCV-related arthropathy can be clinically similar to RA, many patients experiencing the diagnosis criteria stated by American College of Rheumatology (ACR) (15). In this patient s case, the main differential diagnosis reported to senile RA and HCV associated arthropathy. The differentiation consisted in the dosage of the ACCP antibodies, which recorded higher levels and the radiographies of the hand which pointed out periarticular erosions, rare in HCV arthropathy. The comparative immunological studies at patients with chronic hepatitis C virus proved the superiority of ACCP antibodies in RA diagnosis. ACCP antibodies were scarcely positive at patients with HCV and arthralgia (5.7%), absent at the secondary Sjögren syndrome (0%) but they were present at 78% of the patients with RA (1). A previous study used for detecting ACCP antibodies a second generation ELISA kit (cut off = 20U/ml) and reported a prevalence of 6.9% (2/29) in patients with HCV and mixed crioglobulinemia and 0% (0/50) in patients without crioglobulinemia (16). In a different group of 39 patients with HCV, 31 of which with associated arthropathy, compared with 30 patients with RA criteria, ACCP antibodies were present in 77% of the patients with RA and in no patients with HCV (13). Classically, 50% of the patients with VCH present mixed crioglobulines and 24% arthralgia (1). Referring to the primary Sjögren syndrome, the 639

4 Corina Dima-Cozma et al. percentages are small, less than 10 % of the patients with primary Sjögren syndrome presenting ACCP antibodies (17). VCH was associated with many other extrahepatic manifestations as vasculitis, glomerulonephritis, thyroiditis and sialoadenitis, but poliarthritis were most cited (10). Fadda et al. examined 302 patients with VCH for arthritis (8% of the patients with crioglobulinemia presented nonerosive oligoarthritis, 15% of the patients with crioglobulines experienced polyarthritis and 30% of them presented erosions at radiological investigations) (18). Among the self-antibodies produced by the organism in VCH, RF is one of the most frequent (30%-70%), sometimes present at high levels (12). Unlike RF, ACCP antibodies were not mentioned as autoimmune markers and did not record high levels at patients with VCH, included in the published studies (1, 6, 13, 16, 19-21). Lu et al. (19) also studied the diagnostic role of antiagalactosil Ig G antibodies in differentiating RA from the other similar arthropathies, present in VCH, hepatitis B virus or primary Sjögren syndrome. They pointed out that the anti-agalactosil antibodies sensitivity and specificity is lower than that of ACCP antibodies (81% sensitivity and 98.4% specificity), which remain the golden standard in differentiating RA from other arthropaties associated to viral hepatitis and primary Sjögren syndrome, regardless of the presence or the absence of RF. In the study conducted by Ezzat et al. (20), which included 30 patients with RA and 22 with HCV related arthropathy, the sensitivity of ACCP antibodies was comparable to that of RF (83.3% vs 90%), but their specificity was by far higher (95.4% vs. 18.2%). The apparition of ACCP antibodies in RA is the result of the migration of inflammatory cells at the level of joints where the enzyme protein arginil deaminase (PAD) transforms the arginin aminoacid in citrulline, followed by apoptosis of articular cells (22). Up to this moment, there have been used 3 generations of tests to point out the anti-citrulline antibodies, the first generation including only antiperinuclear factor (APF) antibodies and antikeratin antibodies (AKA). In the case of second and third generation tests, sensitivity was increased by using some combinations of synthetic cyclic citrullinated peptides (23). In our case, the immunological investigation was completed by the imagistic assessment which helped completing the RA diagnosis criteria according to the present guides (15). The pain from the level of the cervical spine being intense, vertebral computed tomography excluded the presence of metastases, and the abdominal computed tomography was performed to underline the possible liver tumor formations. Articular symptoms could also be the expression of paraneoplastic rheumatoid syndrome, associated to hepatocarcinoma, although liver tumors are, more frequently, accompanied by various hematological disorders, hypoglycemia, myositis and neurological syndromes. The presence of chronic VCH limits the treatment options of the associated RA. Considering the age too, we chose for our patient the hydroxcloroquine treatment associated with NSAID; the improvements were noticeable after the first weeks of treatment. Other authors also mention the possibility of using hydroxcloroquine and sulfasalazine in patients with moderate liver disorders. Cyclosporine, with antiviral effect as well, but also tumor necrosis 640

5 Differentiation of rheumatoid arthritis from hepatitis C - related arthropathy: case report factor (TNF) inhibitors, rituximab and abatacept were used (3, 24). CONCLUSIONS This case as well as the previous reports in the literature emphasized the particularities of the RA in comparison with hepatitis C-related arthropathy and describe the utility of ACCP as laboratory diagnostic tool. REFERENCES 1. Sène D, Ghillani-Dalbin P, Limal N, et al. Anti-cyclic citrullinated peptide antibodies in hepatitis C virus associated rheumatological manifestations and Sjoögren s syndrome. Ann Rheum Dis 2006; 65: Al Naamani K, Al Sinani S, Deschȇnes M. Epidemiology and treatment of hepatitis C genotypes 5 and 6. Can J Gastroenterol 2013; 27(1): e8 e Kemmer MN, Sherman KE. Hepatitis C related arthropathy: diagnostic and treatment considerations. J Musculoskelet Med 2010; 27(9): Taylor P, Gartemann J, Hsieh J, Creeden J. A systematic review of serum biomarkers anti-cyclic citrullinated peptide and rheumatoid factor as tests for rheumatoid arthritis. Autoimmune Dis 2011; 2: 1 18, doi: /2011/ Rindfleisch JA, Muller D. Diagnosis and management of rheumatoid arthritis. Am Fam Physician 2005; 72(6): Lienesch D, Morris R, Metzger A, Debuys P, Sherman K. Absence of cyclic citrullinated peptide antibody in nonarthritic patients with chronic hepatitis C infection. J Rheumatol 2005; 32: Rivera J, Garcia-Monforte A, Pineda A, Millan Nunez-Cortes J. Arthritis in patients with chronic hepatitis C virus infection. J Rheumatol 1999; 26: Maillefert JF, Muller G, Falgarone G, et al. Prevalence of hepatitis C virus infection in patients with rheumatoid arthritis. Ann Rheum Dis 2002; 61: Ferri C, Antonelli A, Mascia MT, et al. HCV-related autoimmune and neoplastic disorders: the HCV syndrome. Dig Liver Dis 2007; 39 (Suppl 1): S13-S Cacoub P, Poynard T, Ghillani P, et al. Extrahepatic manifestations of chronic hepatitis C. MULTI- VIRC Group. Multidepartment Virus C. Arthritis Rheum 1999; 42: Sène D, Ghillani-Dalbin P, Thibault V, et al. Longterm course of mixed cryoglobulinemia in patients infected with hepatitis C virus. J Rheumatol 2004; 31: Olivieri I, Palazzi C, Padula A. Hepatitis C virus and arthritis. Rheum Dis Clin North Am 2003; 29: Bombardieri M, Alessandri C, Labbadia G, et al. Role of anti-cyclic citrullinated peptide antibodies in discriminating patients with rheumatoid arthritis from patients with chronic hepatitis C infectionassociated polyarticular involvement. Arthritis Res Ther 2004; 6: R137-R Zuckerman E, Keren D, Rozenbaum M. Hepatitis C virus related arthritis: characteristics and response to therapy with interferon alpha. Clin Exp Rheumatol 2000; 18: Aletaha D, Neogi T, Silman JA, et al. An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative Rheumatoid Arthritis Classification Criteria. Arthritis & Rheumatism 2010; 62(9): Wener MH, Hutchinson K, Morishima C, Gretch DR. Absence of antibodies to cyclic citrullinated peptide in sera of patients with hepatitis C virus infection and cryoglobulinemia. Arthritis Rheum 2004; 50:

6 Corina Dima-Cozma et al. 17. Gottenberg JE, Mignot S, Nicaise-Rolland P, et al. Prevalence of anti-cyclic citrullinated peptide and anti-keratin antibodies in patients with primary Sjogren s syndrome. Ann Rheum Dis 2005; 64: Fadda P, La Civita L, Zignego AL, Ferri C. Hepatitis C virus infection and arthritis. A clinicoserological investigation of arthritis in patients with or without cryoglobulinemic syndrome. Reumatismo 2002; 54: Lu MC, Hsieh SC, Lai NS, Li KJ, Wu CH, Yu CL. Comparison of anti-agalactosyl IgG antibodies, rheumatoid factors, and anti-cyclic citrullinated peptide antibodies in the differential diagnosis of rheumatoid arthritis and its mimics. Clin Exp Rheumatol 2007; 25: Ezzat WM, Raslan HM, Aly AA, Emara NA, El Menyawi MM, Edrees A. Anti-cyclic citrullinated peptide antibodies as a discriminating marker between rheumatoid arthritis and chronic hepatitis C- related polyarthropy. Rheumatol Int 2011; 31: Rezuș E, Grigoriu A, Rezuș C. Aggressive nature of rheumatic arthritis with citrullinated cyclic peptide antibodies. Rev Med Chir Soc Med Nat Iasi 2009; 113 (1): Van Venrooij WJ, Van Beers JBC, Pruijn GJM. Anti-CCP antibody, a marker for the early detection of rheumatoid arthritis. Ann N Y Acad Sci 2008; 1143: Raptopoulou AP, Sidiropoulos M, Katsouraki D, Boumpas T. Anti-citrulline antibodies in the diagnosis and prognosis of rheumatoid arthritis: evolving concepts. Crit Rev Clin Lab Sci 2007; 44 (31): Joseph MA. Treatment of rheumatoid arthritis in patients with concomitant chronic hepatitis C infection. Ther Adv Musculoskel Dis 2012; 4 (1): NEWS TARGETED ANTIFUNGAL PROPHYLAXIS IN HEART TRANSPLANT RECIPIENTS Tissot et al conducted a retrospective analysis to identify the risk factors for the development of invasive fungal infection (IFI) after heart transplantation (HTx) and implement a new antifungal prophylaxis policy. For this purpose, clinical characteristics of HTx recipients hospitalized during a seven years period were recorded and risk factors associated with IFI were identified using Cox regression analysis (Period 1). Based on the results of the first analysis, all recipients at high risk for IFI received targeted caspofungin prophylaxis (Period 2 of the study, lasting 3 years). During Period 1, 10% of patients developed IFI after transplantation. The use of posttransplant extracorporeal membrane oxygenation was the strongest predictor for IFI by multivariate analysis, while Aspergillus colonization and renal replacement therapy were significant predictors by univariate analysis. Antifungal prophylaxis was administered to 17% of patients at high risk for IFI in period 1 versus 100% in Period 2. Only 4% of the patients developed IFI during Period 2. Antifungal prophylaxis was associated with a reduction in IFI incidence and mortality. Extracorporeal membrane oxygenation is an important risk factor for IFI after transplantation and requires targeted administration of antifungal prophylaxis (Tissot F, Pascual M, Hullin R, et al. Impact of Targeted Antifungal Prophylaxis in Heart Transplant Recipients at High Risk for Early Invasive Fungal Infection. Transplantation Feb 11). Teodora Vremeră 642