An Elderly RA Patient with Hepatitis B and Latent TB Save

I have a 70 year old Vietnamese patient who has seropositive RA (+RF, CCP-) manifesting as symmetrical polyarthritis, 10 swollen joints, an elevated ESR 95 mm/hr, and erosions on X-rays. He also has chronic hepatitis B virus (HBV) infection (HBsAg+, high viral load, normal hepatic enzymes) with latent tuberculosis infection (LTBI). He has been on SSZ and HCQ with persistent active disease and an ESR of 45 mm/hr. He is not therapy for hepatitis B but his hepatologist is willing to start prophylaxis. What is the best strategy to improve his disease control without reactivating tuberculosis or hepatitis B in this older patient who has several comorbidities and is at risk for complications of therapy? By the way, he is on Medicare; please consider costs as well. - Stumped in the South

The concern with this patient is that a chosen therapy may lead to reactivation of latent intracellular pathogens; in the case either HBV or TB. However, this patient has several primary risk factors for reactivation of either tuberculosis and HBV, including his age, birth origin (Vietnam), immunosuppression (from active RA) and having high inflammatory burden evidenced by his synovitis and acute phase reactants. Uncontrolled disease and high inflammation (even on low risk DMARDs) are ongoing risk modifiers in this patient. The fact that he has two potentially serious infections truly complicates the formulation of any therapeutic plan. As there is little data on how to manage dual infectious risks, the treatment options in the setting of hepatitis and TB will be addressed separately.

Hepatitis/Hepatotoxic Risks.  There are several drugs that would best be avoided with known liver disease, including methotrexate, leflunomide and NSAIDs. The hepatoxicity risk of tocilizumab and tofacitinib and the known risk of HBV reactivation with rituximab should obviate the use of these agents. Conversely, there are several drugs that may be safely used in someone with known liver disease. These include corticosteroids, hydroxychloroquine, gold salts, cyclosporine, azathioprine, mycophenolate and anakinra. Several of these are the same agents used to immunosuppress patients after renal and hepatic transplants.

Many biologics carry a potential risk of HBV reactivation. This risk is highest in those who are HBsAg+ and those with very high viral DNA levels. Although risk is considerably less in patients with resolved HBV (HBsAg-, HBcAb+), this can be augmented with states of profound immunosuppression (e.g., with cytotoxic chemotherapy). The highest risk of HBV reactivation has repeatedly been reported with TNF inhibitors and rituximab use. While the TNF inhibitors have been shown to be reasonably safe in patients with hepatitis C or resolved hepatitis B (HBcAb+, HBsAg-), their use should be avoided in patients with active, HBsAg+, HBV infection (especially infliximab). Rituximab use has also been repeatedly associated with HBV reactivation in patients receiving B cell inhibition for either RA or lymphoma (Citation source http://buff.ly/1LANvTv).  Thus, rituximab is relatively contraindicated in a patient with measureable viral DNA loads and HBsAg positivity.  

There are fewer reports about the safety of abatacept or tocilizumab in patients with HBV (Citation source http://buff.ly/1LANvTv). HBV reactivation has resulted when HBsAg+ RA patients received abatacept without antiviral prophylaxis and was avoided if they were prophylaxed. There are also cases of HBV reactivation occurring with resolved/occult infection (HBsAg-, HBcAb+) no on prophylaxis. These cases often occurred many months after starting abatacept.  By contrast, tocilizumab (TCZ) has been safely administered to several HBV patients - some after reactivation by TNF inhibitor and others after receiving anti-viral treatement. Cases of reactivation on tocilizumab appear to be few, based on what has appeared in the literature. 

Finally, some at risk patients may require aggressive biologic therapy to treat aggressive RA. The above biologic agents may be used as long as they receive continuous antiviral prophylaxis (e.g., entecavir, tenofovir, lamivudine, etc.). Preventative therapy should be given with the guidance of an experienced hepatologist. Prophylaxis will lower but not nullify the reactivation risk. Thus, the biologic with the least HBV reactivation risk should be considered first (anakinra or tocilizumab, then abatacept, rituximab or TNF inhibitor).

Mycobacterial Risk.  The prescribing rules here are more logic and evidence driven and based on the known pathogenesis of granuloma breakdown and TB reactivation; wherein tumor necrosis factor (TNF) and to a far lesser extent, interferon gamma are responsible for the granuloma formation and maintenance. Thus, inhibition of TNF (or IFN) will result in granuloma breakdown and spread of TB. Playing essentially no role would be the inhibition of T cells, B cells, IL-1, IL-6, CTLA-4, or Janus kinases (and other intracellular mediators) or CD80/86 costimulation. You may then ask why the prescribing guidelines for abatacept, tocilizumab, tofacitinib and leflunomide call for pretreatment testing of TB infection (just as with the TNF inhibitors)?  The reason is that they were done in their drug development trials. Note that TB testing is not required with the use of rituximab, anakinra, apremilast, cyclosporine or methotrexate and for the same reason - they were not required or done in the developmental trials. Another weak reason would be that there are reports of TB and other mycobacterial infections occurring in patients on ABA, TCZ and TOFA. However the few TB reports with these agents is miniscule compared with the frequency seen in patients on TNF inhibitors. A metanalysis of 100 clinical trials with 75000 patients and 63 extension studies with a total of 80774 patient-years of biologic exposure. They identified 31 TB cases with TNF inhibitors, 1 with abatacept and none with rituximab, tocilizumab, ustekinumab or tofacitinib.  Hence, with the risk of TB is considerably lower in the non-TNF biologics and is probably the lowest with anakinra, abatacept, rituximab and tocilizumab.

In summary, there are three treatment options that could be considered for this elderly patient who is at risk for TB and HBV reactivation:

1. Avoid biologic agents (owing to the known risks of few and the uncertain low risks of many) and use a DMARD or combination of DMARDs to control his disease, with or without low-dose prednisone and analgesic therapy. Methotrexate and leflunomide would be contraindicated in this patient.
2. Use a low-risk biologic in conjunction with anti-viral prophylaxis to prevent HBV reactivation and monitor for signs and symptoms of TB activity. I would recommend tocilizumab or abatacept along with a hepatology consult and anti-viral prophylaxis. Note: there is no value to PPD or IGRA (e.g., quantiferon) testing or CXR monitoring above that of monitoring for signs and symptoms.  Also, there is no role for prophylactic anti-tuberculous therapy in this elderly patient.
3. Use low risk biologic without viral prophylaxis and monitor for reactivation. Options here would be limited to anakinra or possibly tocilizumab. However, most would recommend viral prophylaxis along with tocilizumab use.