Hepatitis C Virus
- Diagnosis by positive anti–hepatitis C virus (HCV) antibody confirmed by a sensitive, qualitative HCV RNA assay.
- Arthralgias and rarely a nonerosive arthritis are seen in patients with chronic HCV infection, with or without associated cryoglobulinemia.
- Coexistent rheumatoid arthritis (RA) and HCV infection can create diagnostic and therapeutic problems.
Chronic hepatitis C is second only to hepatitis B (see next section) among the common chronic viral infection worldwide, with an estimated 170 million people infected. In the United States, chronic HCV infection affects 4.1 million people, represents the leading cause of liver transplantation and death from liver disease, and has surpassed HIV infection as a cause of death.
HCV, an RNA virus, is transmitted by the parenteral route. The most common causes of HCV transmission are injection drug use and transfusion of blood or blood-derived products before 1992. Infrequent modes of transmission include accidental exposures at work (eg, health care workers), sex, and childbirth. In a number of cases, no identifiable risk factor can be found. There is currently no vaccine available for HCV. Screening of blood products has almost eliminated the risk of post-transfusion hepatitis C. The persons at greatest risk for HCV now are injection drug users and persons with high-risk sexual behavior (multiple sexual partners).
Less than 20% of patients with acute HCV infections are symptomatic at the time of infection. Most cases of HCV, however, are associated with transition to chronicity (55–85%). The natural history of chronic HCV infection is variable. Between 5% and 20% of chronically infected HCV patients develop cirrhosis within several decades. Among cirrhotic patients, within 10 years 30% develop end-stage liver disease and 10–20% develop hepatocellular carcinoma. Factors associated with more rapid disease progression include older age, alcohol abuse, coinfection with HIV (see Chapter 51), and the presence of hepatic steatosis.
Chronic HCV infection is uniquely associated with a number of extrahepatic rheumatic manifestations including arthralgias, arthritis, sialadenitis (Sjögren-like), and cryoglobulinemic vasculitis.
HCV replicates predominantly in hepatocytes after entrance into the circulation. Following acute infection, HCV RNA can be detected in the serum within 1 week. Alanine aminotransferase elevation occurs 2–3 months later. Anti-HCV antibodies can be found 1–2 months after acute infection. Acute HCV infection is not associated with rheumatic complaints (in contrast to acute hepatitis B), and many patients do not know that they are infected.
HCV exhibits tropism for hepatocytes, B lymphocytes, and salivary and lachrymal gland epithelial cells. Monoclonal and polyclonal B-cell expansions have been found in the liver and bone marrow of chronically infected patients. In approximately half of patients with chronic HCV infections, circulating cryoglobulins can be detected. However, only a minority of these patients (<5%) develop the syndrome of mixed cryoglobulinemia (see Chapter 36). Deposition of immune complexes containing cryoglobulins in different organs is the presumed disease mechanism in mixed cryoglobulinemia, characterized by purpura, arthralgias (or more rarely, arthritis), glomerulonephritis, and polyneuropathy.
Hepatitis C–Associated Arthralgias & Arthritis
- Chronic HCV infection diagnosed by positive anti-HCV antibody and confirmed by a sensitive, qualitative HCV RNA assay.
- Usually manifests as polyarthralgias, less often as a nonerosive arthritis.
- Coexisting RA and HCV infection can create diagnostic and therapeutic problems.
Polyarthralgias without detectable joint swelling occur in approximately 20% of patients with chronic HCV infection. An inflammatory oligoarthritis or polyarthritis develops in between 2% and 5% of HCV-infected patients. The arthritis associated with HCV infection is relatively benign and does not lead to juxta-articular erosions or joint destruction. The majority of cases (˜80%) of HCV-associated arthritis have polyarticular involvement of small joints in a RA-like distribution; a minority have monoarticular or oligoarticular involvement of large joints. Morning stiffness is present in two thirds of patients.
Diagnosis of HCV infection is made initially by the detection of anti-HCV antibodies by enzyme immunoassays. A positive test should be confirmed by a qualitative assay designed to detect serum HCV RNA (by polymerase chain reaction or branched-DNA assays).
Unselected patients with chronic HCV infection display a number of autoantibodies including rheumatoid factor (40–65%), cryoglobulins (40–55%), antinuclear antibodies (10%), and antithyroid antibodies (<10%). None of these abnormalities distinguish those with articular symptoms from those without. Patients with HCV-associated arthralgias and arthritis do not have antibodies against cyclic citrullinated peptides (anti-CCP) and do not develop radiographic erosions or other findings. In patients with HCV-associated mixed cryoglobulinemia, rheumatoid factor positivity (virtually 100%) and low C4 levels (50–85%) are characteristic laboratory findings.
It should always be kept in mind that since chronic HCV infection is not uncommon in the general population (˜2%), any rheumatic condition can coexist with HCV infection. Differentiating between the arthritis associated with HCV and RA that has developed in a HCV-infected individual can be particularly difficult because the patterns of joint involvement are similar and both can have positive tests for serum rheumatoid factor. The presence of anti-CCP antibodies (present in 70% of RA patients) or erosive changes on radiographs of the hand or foot radiographs point to coexisting RA. If antinuclear antibodies are present, the differential diagnosis should include systemic lupus erythematosus.
The treatment of arthritis in the context of HCV infection is always a challenge. Patients with HCV-associated arthritis in the absence of cryoglobulinemia have been treated successfully with nonsteroidal anti-inflammatory drugs, hydroxychloroquine, and low-dose prednisone. Administration of antiviral treatment (interferon-α) has not been associated with significant improvement, and in certain cases has exacerbated the articular symptoms.
The treatment of RA in patients with coexisting HCV infection is also problematic. In mild cases, hydroxychloroquine can be tried first with or without low-dose prednisone (<7.5 mg/d). Disease-modifying drugs such as methotrexate and leflunomide are potentially hepatotoxic and should be used with extreme caution, if at all. Tumor necrosis factor-α inhibitors have also been used in patients with HCV infection without significant short-term side effects.
The prognosis of HCV-associated inflammatory arthritis is good. According to a recent study of a large population of patients with HCV-associated cryoglobulinemia, mild disease activity is seen in half of the patients, whereas one third follow a moderate to severe course. Non-Hodgkin lymphomas can develop in some patients.
Hepatitis B Virus
- Symmetric, self-limited polyarthritis accompanied by rash developing during the pre-icteric phase of acute hepatitis B.
- Diagnosis by hepatitis B surface antigen and IgM anti–hepatitis B core antigen.
Hepatitis B virus (HBV) infection is currently the most common chronic viral infection worldwide. It is estimated that 2 billion people have been exposed to the virus and 350 million are chronically infected. Every year 1 million people die of HBV-related complications, including end-stage liver disease and hepatocellular carcinoma.
HBV is an enveloped DNA virus that is transmitted parenterally, sexually, or vertically (during either childbirth or early childhood). HBV infection during the perinatal and early childhood period, though usually asymptomatic, is associated with a high rate of transition to chronicity (30–90%). In contrast, exposure to HBV during adolescence or adulthood leads to the syndrome of acute hepatitis B, followed by clearance of the virus in >95% of the cases (immunocompetent persons).
During the pre-icteric phase of acute hepatitis B, a symmetric polyarthritis accompanied by skin rash may occur. Joint complaints subside when the symptoms and signs typical of acute hepatitis (eg, jaundice) develop. Polyarthritis has been rarely reported during the course of chronic HBV infection, although it is difficult to establish a clear pathogenetic role for HBV in these cases. Polyarteritis nodosa (see Chapter 35) is a vasculitis affecting medium-sized vessels that can develop during the first few months of acute HBV infection, or more rarely during chronic HBV infection.
Both rheumatic syndromes associated with HBV infection are considered to be immune complex–mediated. The composition of the pathogenic immune complexes is a matter of controversy. Circulating HBV antigens (hepatitis B surface antigen and hepatitis B e antigen), their respective antibodies (anti–hepatitis B surface antigen and anti–hepatitis B e antigen), and complement have been detected in joints and involved blood vessels. The reason for the development of polyarteritis nodosa in some patients remains unclear.
