Educating Rheumatologists on Hepatic Associations With Rheumatic Diseases

Historic advances have been occurring in hepatitis C therapy during the last decade. This once difficult-to-treat chronic infection is essentially curable with direct-acting antiviral therapies. For hepatitis B, a wave of biologic therapies is changing the landscape and offering hepatologists, gastroenterologists and infectious diseases clinicians a host of options to manage patients.

News of these advances has been making headlines in the mainstream media, but this information has yet to take root among many rheumatologists who manage patients with hepatitis. Understanding the therapeutic armamentarium remains low. Adherence to screening protocols for both hepatitis B and C is subpar. Looking from the other end, arthritis and various vasculitides are common among patients with hepatitis. Underlying these complications is the ever-present concern about using immunosuppressive therapies in patients with, or at risk for, a viral infection or reactivation.

Leonard H. Calabrese, DO, professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and Chief Medical Editor of Healio Rheumatology, laid out the basics.

“At 30,000 feet, chronic viral hepatitis B and C are comorbidities that greatly affect the treatment of rheumatic disease in several ways,” he said. “First, what has been focused on for many years is the fact that HBV and HCV can result in the development of rheumatic diseases.”

He cited HCV-associated cryoglobulinemia and arthritis and HBV-associated, life-threatening vasculitis as critical examples. “Yet that’s only part of what this should be focused on,” he said. “These are rare diseases, with incidence rates that are diminishing in recent years.”

Far more important now, according to Calabrese, is the notion that there are large numbers of patients who have a rheumatic disease, like rheumatoid arthritis (RA) or spondyloarthritis, and have chronic viral hepatitis as a comorbidity.

“This comprises a major challenge in the management of autoimmune disease,” he said. “We are using immunosuppressive drugs in people with chronic viral infections. This is something that requires a great deal of care and caution.”

He said the two main challenges for rheumatologists are: What are the recommendations for screening viral hepatitis in patients with immune-mediated inflammatory disease who are about to receive immune therapy? And once we detect the disease, how do we manage it?

Tram T. Tran, MD, medical director of liver transplant at Cedars Sinai, underscored many of Calabrese’s suggestions about screening and immunosuppression.

“Now, we are starting to recognize that many patients have flares with abnormal liver enzymes in the setting of immune treatments for rheumatological disorders,” she said. “This raises the opportunity for us to ensure rheumatologists are well-versed on the various risks, including the risk for viral reactivation.”

Understanding the complicated process of screening for HBV and the slightly less complicated screening process for HCV, is a good place to start, Tran said. Being familiar with the treatment landscape — from reactivation risks associated with rituximab (Rituxan, Genentech) and anti-CD20 agents to the relatively user-friendly HCV antivirals — will also be useful to rheumatologists.

“The next thing to consider is the association between viral hepatitis and rheumatic diseases,” Tran said. “There is an abundance of literature showing associations with vasculitis and arthritis. This should be on the radar among both rheumatologists and hepatologists. If a patient is presenting with a rheumatic disorder, then hepatitis may be involved.”

Screen, Screen, Screen

Sebastiani and colleagues aimed to gain further understanding of HBV management in patients with RA in Italy with the goal of producing a set of useful recommendations. They concluded that HBV infection is not uncommon in clinical practice, but that screening for the infection among patients with early arthritis has failed to reach universal acceptance. However, it is considered a necessity before initiation of immunotherapy. They added that biologic therapies carry risk in this patient population and that patients with RA and active HBV should be co-managed with a hepatologist. The hepatitis infection should be controlled or supressed with antiviral therapy before immune therapy can begin, while occult carriers of HBV should be monitored or undergo prophylactic treatment based on reactivation risk.

For Robert J. Fontana, MD, medical director of liver transplantation and professor of medicine at the University of Michigan, a significant barrier to uptake of screening recommendations among rheumatologists is the complexity of the HBV screening process itself.

“There are three markers for hepatitis B,” he said. “There is the hepatitis B surface antigen, anti-HBV core antibody and anti-HBV surface antibody tests that you can order.”

If the patient is negative for all three, then nothing needs to be done beyond primary vaccination with the standard HBV vaccine, according to Fontana. “If the patient is positive, then it depends on the pattern of positivity whether they have active disease and whether it is likely or not to reactivate,” he said. “It gets more complex.”

Fontana described the process of HBV screening as “hard to message.” This can, in turn, have an impact on uptake rates.

“The interpretation of HBV serologies is where people get tripped up,” he said. “If the patient has surface antigen positivity, no matter what the other two tests show, they have HBV. These patients are infectious to other people and should be rapidly referred to a liver specialist or a GI doctor.”

For hepatitis C, there is the anti-HCV antibody test and the polymerase chain reaction (PCR) RNA test. “If the patient is PCR positive for HCV, then they have HCV infection and can transmit,” Fontana said. “These patients should be referred to a liver specialist for direct-acting antiviral therapies.”

Despite the complexity of the process, screening is imperative, according to Eric L. Matteson, MD, professor of medicine in the division of rheumatology at the Mayo Clinic College of Medicine and Science.

“All patients with rheumatic diseases for whom immunosuppressive therapy is being considered should be evaluated for hepatitis B and C,” he said.

Calabrese, who is also RJ Fasenmyer Chair of Clinical Immunology, agreed. “How do rheumatologists screen patients for HBV in their practice?” he said. “I wrote a letter on screening guidelines to the editor of Arthritis Care & Research last year. In short, current screening guidelines from the [American College of Rheumatology] ACR are outdated and outmoded. Data out there show that rheumatologists are not doing a great job of screening patients for viral hepatitis before starting immunotherapy.”

Elizabeth D. Ferucci, MD, MPH, rheumatologist at Alaska Native Tribal Health Consortium and affiliate associate professor of Medicine at the University of Washington, said testing for HBV and HCV infection is standard practice for new patients at the Alaska Native Medical Center’s rheumatology clinic.

“This is beneficial for several reasons,” she said. “First, it is not uncommon to make a new diagnosis of HCV infection in a patient presenting with joint pain and a positive rheumatoid factor. Second, knowing a patient’s exposure status to HBV and HCV will help in selecting and monitoring [disease-modifying antirheumatic drug] DMARD/biologic medications. For example, reactivation of hepatitis B even if the infection has been cleared has been reported with rituximab.”

She said at the Alaska Native Tribal Health Consortium, they screen for HBV with hepatitis B core antibody, not immunoglobin (Ig)M but IgG.

“If this is negative, then we stop because it indicates no previous exposure to HBV. If positive, our laboratory automatically performs hepatitis B surface antigen and hepatitis B surface antibody. If hepatitis B surface antigen is negative, this indicates past exposure and we need to use caution with rituximab,” she said.

Kevin L. Winthrop, MD, MPH, professor at Oregon Health & Science University, suggested that data may help answer some of these questions.

“I would love to do a survey now to see what percentage of rheumatologists are screening for HBV and how they are actually doing it,” he said, and offered a practical solution to dealing with the complexity of the screening procedures for hepatitis. “You can make a persuasive argument that it makes sense to do all three screening tests at the same time: HBV surface antigen, HBV surface antibody and HBV core antibody.”

Calabrese also suggested that guidelines are unclear in terms of identifying risk factors. “Rheumatologists only check them before certain drugs, but not before initiating other drugs,” he said. “The guidelines need to be more broad-based, with clearer language.”

“The vast majority of people with HBV in this setting have it already and they are at risk for reactivation with certain forms of immunosuppression making screening imperative,” Winthrop said. However, Winthrop continued “We should think of preventing new infections and identify patients who might benefit from vaccination, and for this we need to be looking at risk factors for HBV exposure.”

Rheumatologists should ask patients about risk factors for hepatitis infections, according to Winthrop. “Anything where blood products can be swapped is a risk factor — risky sex, IV drug use, transfusions. Most people I see in this practice don’t have these risk factors. In truth, it’s a small number of people, but it is worth thinking about and asking about,” he said.

Hepatitis B is most frequently seen in people migrating from areas where that disease is endemic, according to Winthrop. “The more we understand where these diseases are coming from, the better we’ll be able to manage them,” he said.

Fontana built on this point, suggesting that it is simply a numbers game. “In the United States, anywhere from 1.5% to 2% of all adults have HCV,” he said. “The proportion who have HBV is a little less than 1%, but this is almost 2 million people. If you start to look for it, you will find it.”

Immunosuppressed Patients

Matteson suggested that a critical challenge faced by rheumatologists is the threat of viral reactivation with immunosuppressive therapies. “A number of the medications used for the management of rheumatic diseases impair the body’s ability to deal with chronic hepatitis B and C,” he said. “There are effective treatments for both of these forms of hepatitis. For patients who have child Pugh score of A and are on hepatitis treatment, biologics and non-hepatotoxic immunosuppressives, such as azathioprine, can be considered.”

The increasing availability of biologics and potent immunosuppressive drugs in the marketplace are complicating treatment strategies, according to Fontana. “A lot of the newer drugs like rituximab have been associated with HBV reactivation,” he said. “Often, they have a black box warning, which puts that risk information front and center. Now, does that mean you can’t use Rituxan? You can. It is unlikely you’ll get reactivated and a bad flare.”

Calabrese expressed more caution. “There are a few key elements to consider,” he said. “First, we need to steer away from certain therapies like rituximab and look at other drugs and mechanisms,” he said. “Then, you have to monitor the patient appropriately and classify them in terms of risk. If they reactivate, treat them with antivirals.”

A key message from Fontana is that anyone who is planning to treat with infliximab or rituximab, more than 4 weeks of steroids or cyclophosphamide should be aware of the possibility of reactivation. “If all markers are negative, go ahead and treat the patient,” he said. “But when markers become positive, the question is whether the rheumatologist should deal with it or pass it off to a hepatologist or GI specialist. In a big medical center, it’s easy because there are specialists on hand. In other areas, this may not be the case.”

Hepatitis B Reactivation

Karvellas and colleagues performed a retrospective, multicenter review of 156 consecutive patients diagnosed with HBV-associated acute liver failure after. Participants were on the Acute Liver Failure Group Registry between January 1998 and April 2015. Results showed 18% of cases occurred among patients who had been treated with immunosuppressive therapy, while 82% were among those that did not. Immunosuppressed patients with HBV-associated acute liver failure were more likely to be non-white and have either anemia or thrombocytopenia compared with the non-immunosuppressed group. The groups did not differ in terms of serology of the HBV infection, severity of liver failure, status of hepatic encephalopathy or necessity of mechanical ventilation, vasopressors or renal replacement therapy. The 21-day survival rate among immunosuppressed patients with acute liver failure was 42.9% compared with a 62.5% survival rate among the non-immunosuppressed patients. When the investigators assessed the cohort for 21-day transplant-free survival, they found associations with increased MELD score (OR = 0.89 per increment), need for mechanical ventilation (OR = 0.11) and immunosuppressive therapy (OR = 0.27). “Patients undergoing chemotherapy should be screened for HBV infection and given appropriate anti-viral therapies to reduce preventable mortality,” the researchers concluded.

“This study documents that nearly 20% of the HBV-related acute liver failure we see in the United States each year is due to HBV reactivation from either rheumatology drugs or chemotherapy drugs,” Fontana said. “That incidence is entirely preventable if we could get everyone screened, triaged and high-risk patients treated.”

Similarly, Lin and colleagues retrospectively analyzed HBV reactivation risk in a cohort of 3,125 patients with systemic lupus erythematosus undergoing immunosuppressive therapy. The study included patients from a single center in Taiwan between January 2001 and December 2012. Among 906 patients who underwent HBV screening tests, 38 patients demonstrated HBVsAG positivity. Reactivation occurred in 39.5% of this group, while severe hepatitis flare occurred in 53.3%. Among 157 patients with HBVsAG-negativity/anti-hepatitis B core IgG antibody-positivity, 1.9% experienced sero-reversion of HBVsAG during immunosuppression. However, none of the five patients treated with prophylactic or pre-emptive antivirals flared. Prednisone at a dose of higher than 5 mg was associated with HBV reactivation risk, according to the researchers. “The risk of hepatitis B virus reactivation is high in lupus patients receiving immunosuppressive therapy,” they wrote. “Antiviral prophylaxis or pre-emption can effectively reduce the incidence of HBV reactivation in lupus patients.”

Tran spoke directly to the mechanism of reactivation. “In the setting of immune suppression, HBV disease is not caused by the virus but by the immune system,” she said. “Specifically, it is caused by the active inflammation of T cells, which triggers inflammation of the immune system. If you suppress the immune system, the virus becomes active.”

The problem, however, is that it is entirely possible for a clinician to treat a number of patients with these immunosuppressive drugs and never see a reactivation event, according to Fontana. “Patients have normal liver enzymes, the drugs work, reactivation doesn’t occur,” Fontana said. “Clinicians get skeptical, but I need to stress that these events happen.”

Hepatitis C Therapies

Shahin and colleagues compared outcomes in a group of patients treated with antiviral therapies containing sofosbuvir (Sovaldi, Gilead) with those from a historical cohort of patients treated with interferon-based therapies. The first group included 15 patients with arthralgia or arthritis and nine patients with vasculitis. Seventeen of these patients received sofosbuvir and ribavirin, while seven were treated with sofosbuvir and simeprevir (Olysio, Janssen). The historical cohort included 15 patients with arthropathy who were treated with interferon and ribavirin. The sustained virologic response rate was 100% in the sofosbuvir group and 80% in the interferon group, according to the findings. Significant improvements were reported for the sofosbuvir group in terms of tender joint count and VAS for pain. Improvements also occurred among patients with vasculitis treated with sofosbuvir. Clinicians noted the disappearance of purpura, arthralgia and leg ulcers, despite persistent neuropathy. Apart from one patient who experienced deterioration of arthralgia, the adverse event profile for sofosbuvir showed mild effects. In the interferon arm, tender joint count increased, as did swollen joint count and VAS. “The use of [interferon]-free regimens is safe and effective in the treatment of most HCV-related rheumatologic [extra-hepatic manifestations],” the researchers concluded.

HCV therapies are easy to use, with often one pill a day for 8 weeks or 12 weeks. “Most patients can be treated successfully, so refer them,” Winthrop said. “Also, it is important to consider that treating the HCV might help with more than just the HCV. It might help with joint and rheumatic manifestations of HCV.

“The ACR guidelines for management of rheumatoid arthritis address hepatitis specifically, but certainly efforts at awareness are important for rheumatologists to be able to manage their patients effectively,” Matteson said.

Calabrese amplified this point. “This has the potential to change our lives because interferon-based therapies were terrible for patients with autoimmune diseases,” he said. “There were side effects, there were issues with underlying diseases. But now we have direct-acting antiviral drugs, and the importance of these therapies can’t be understated. We are living through medical history in that we are on the verge of curing HCV. We can cure our patients of HCV with 12 weeks of therapy and then we can treat them with whatever we want, provided they don’t have cirrhosis. But this news is still eye-opening to rheumatologists.”

A possible reason for this lack of awareness is that direct-acting antiviral therapies are largely prescribed by a hepatologist, infectious diseases clinician or gastroenterologist, according to Fontana. “Whenever a drug is limited to use by a specialist, as these therapies are, a lot of other doctors say they can’t keep track of the FDA approvals,” he said. “Every doctor should know that HCV can be cured simply with short-term oral therapy.”

Fontana encouraged rheumatologists to pay a bit more attention to findings outside of the field. “We all tend to read our own literature and these things are not emphasized in the annual review, so they are under our radar,” he said.

“It should be noted that these therapies are expensive,” Fontana added.

HCV-associated Cryoglobulinemic Vasculitis

Ignatova and colleagues investigated a cohort of 72 patients with HCV-associated cryoglobulinemic vasculitis (CV) to determine strategies for optimizing treatment regimens and survival. Antiviral therapy led to sustained virologic response in 48% of the cohort and clinical remission occurred in 68%. Rituximab was associated with a 73% remission rate compared with a 13% remission rate among traditional immunosuppessants. The researchers noted the combination of rituximab and antiviral therapy was most effective in patients with severe vasculitis. “HCV-associated CV can determine the prognosis of chronic HCV infection,” the researchers concluded. “[Antiviral therapy] is the treatment of choice in all patients with HCV-associated CV.”

Tran offered a simple approach to dealing with this particular crossover patient population, one she hopes may become a refrain for rheumatologists moving forward. “There are highly effective hepatitis C treatments available,” she said. “If you screen for HCV and treat it, it often resolves.”

Ferucci and colleagues investigated prevalence rates of HCV-associated inflammatory arthritis. They analyzed clinical and immunological characteristics in a cohort of 117 patients from a population-based cohort with chronic HCV in Alaska who had not been treated for HCV. Results showed 6.8% of the cohort had HCV-associated arthritis. The HCV patients with arthritis tended to be younger than those without arthritis and were also more likely to have rheumatoid factor. Anti-nuclear antibodies also were more common in the group with arthritis than in the group without arthritis (63% vs. 23%). Self-reported joint swelling occurred in 75% of patients with HCV-associated arthritis and in 26% of those not in the HCV-associated arthritis group. Features of fibromyalgia also occurred more frequently in the arthritis group, as did a decrease in functional status. The researchers failed to observe any differences in cytokines between the two groups. Links between arthritis or autoantibodies and liver-related outcomes also did not occur. “In this study of a cohort of individuals with chronic HCV infection, HCV-associated arthritis was present in less than 10%,” the researchers concluded. “Few serologic features distinguished participants with or without arthritis.”

Ferucci put the results into context. “The figure of less than 10% represents the proportion of people with chronic hepatitis C infection who have true HCV-associated inflammatory arthritis,” she said. “Overall, this is high when you consider that rheumatoid arthritis — which has some similarities to this type of arthritis — is present in less than 1% of the overall adult population. However, keep in mind that a much larger proportion of people with hepatitis C have joint symptoms, such as joint pain, and that people with hepatitis C often have both joint pain and a positive rheumatoid factor, the combination of which can be mistaken for rheumatoid arthritis.”

“We see chronic inflammation in our patients, but we still don’t understand it well,” Tran said. “Symptomatically, it seems to be associated with HCV, so we should be observing to see if the symptoms resolve. Rheumatologists should be aware that if they catch hepatitis C more often, many of these patients would have relief from their clinical symptoms. Having it on their radar is valuable.”

Despite the similarities between HCV-associated arthritis and RA, the important differences are that the arthritis is non-erosive and anti-CCP antibodies are negative in HCV-associated arthritis, according to Ferucci.

“The HCV-associated arthritis is often mild and can be managed with DMARDs, such as hydroxychloroquine and sulfasalazine,” she said. “There are also several studies demonstrating that [tumor necrosis factor] TNF inhibitors are safe in patients with hepatitis C, so these can be used in more severe arthritis.”

Data from older interferon-based HCV treatments showed the arthritis improved with treatment of the underlying viral infection, according to Ferucci. “It is likely that the direct acting antiviral agents will have similar success, but this has not yet been studied with respect to arthritis,” she said.

Wijarnpreecha and colleagues conducted a meta-analysis of Medline and Embase databases to assess osteoporosis incidence rates among individuals with HCV. The analysis included four studies that met eligibility criteria. Osteoporosis risk was elevated in the HCV groups (OR = 1.65). A statistically significant association was observed when the researchers included studies of a higher quality (OR = 2.47).

“The study found that patients with hepatitis C are at higher risk of osteoporosis, which is not surprising as patients with hepatitis C have a chronic illness which affects, or confounds, a person’s well-being,” Matteson said. “This includes the risk of developing other chronic conditions like osteoporosis and may be physiologically linked due to chronic liver disease. It underscores the importance of screening patients with chronic hepatitis for osteoporosis and managing both conditions appropriately.”

Moving Forward

Summing up, Ferucci focused on the easiest challenge: treating hepatitis C. “With the new highly effective HCV treatments, these patients should be identified and treated,” she said.

Fontana closed by stressing the importance of understanding the screening processes for hepatitis B and C, and that patients should know their status before initiating immunosuppressive therapies. “We need to know better how to prevent reactivation in high-risk scenarios, and we need to know how to manage patients if reactivation isn’t prevented,” he said. “We’re not pointing fingers, we just want to educate people.”

For Tran, finding time to screen and manage these patients may become easier for clinicians in coming years.

“The good news is that these comorbidities are recognized by the CDC,” she said. “We started with screening all baby boomers, which eliminates the need to assess risk factors. If we can reach a similar place for arthritis, clinicians can just screen for hepatitis and check off that box.”

The importance of having more treatment options, particularly for hepatitis B, can’t be under-stated, according to Winthrop. “The government and the academics need to get together and find therapies to eliminate hepatitis B the same way they did with hepatitis C,” he said. “Curative therapies would solve a lot of problems.”

For now, for Calabrese, communication between clinicians in the two specialties is key. “This is an inter-professional challenge,” he said. “We need to recognize where there are seams between the specialties. The way to manage that is to screen, screen, screen.” — by Rob Volansky

• References:
• Ferucci ED, et al. Semin Arthritis Rheum. 2017;doi:10.1016/j.semarthrit.2017.04.004.
• Gandhi NP, et al. J Clin Rheumatol. 2017;doi:10.1097/RHU.0000000000000536.
• Ignatova TM, et al. Ter Arkh. 2017;doi:10.17116/terarkh201789546-52.
• Karvellas, CJ, et al. Clin Gastro Hep. 2017;doi:10.1016/j.cgh.2016.06.008
• Lin WT, et al. Lupus. 2017;doi:10.1177/0961203317711009.
• Loomba R et al. Gastroenterology; 2017;doi:10.1053/j.gastro.2017.02.2009.
• Sebastiani M, et al. Joint Bone Spine. 2017;doi:10.1016/j.jbspin.2017.05.013.
• Shahin AA, et al. J Rheumatol. 2017;doi:10.1007/s00393-017-0356-7.
• Wijarnpreecha K, et al. Saudi J Gastroenterol. 2017;doi:10.4103/sjg.SJG_452_16.

• For more information:
• Leonard H. Calabrese, DO, can be reached at 9500 Euclid Ave. #A50, Cleveland, OH 44195; email: calabrl@ccf.org.
• Elizabeth D. Ferucci, MD, MPH, can be reached at 3900 Ambassador Dr., Suite 201, Anchorage, AK 99508; email: edferucci@anthc.org.
• Robert J. Fontana, MD, can be reached at 3912 Taubman Center, Ann Arbor, MI 48109; email: rfontana@med.umich.edu.
• Eric L. Matteson, MD, can be reached at 200 First St. SW, Rochester, MN 55905; email: matteson.eric@mayo.edu.
• Tram T. Tran, MD, can be reached at 6500 Wilshire Blvd., Suite 1900, Los Angeles, CA 90048; email: tram.tran@cshs.org.
• Kevin L. Winthrop, MD, can be reached at 3181 SW Sam Jackson Park Rd., Portland, OR 97239; email: winthrop@ohsu.edu.

Disclosures: Calabrese reports he is a consultant for Genentech, Pfizer, Bristol-Myers Squibb, GSK, Sanofi, Jansen and AbbVie; and is on the speakers bureau for Genentech, AbbVie, Bristol-Myers Squibb and Crescendo Bioscience. Fontana reports he conductis research funded by Gilead Sciences, AbbVie Labs and BristolMyersSquibb in viral hepatitis. Tran reports she consults for AbbVie, Gilead and Merck. Winthrop reports he consults for and receives a research grant from Bristol-Myers Squibb; is a consultant for AbbVie, Galapagos, Genentech/Roche, Eli Lilly, Pfizer and UCB. Ferucci and Matteson report no relevant financial disclosures.