New Guidance for Managing HCV-Related Cryoglobulinemic Vasculitis

Three articles in separate journals last week related to the vexing problem of potentially fatal cryoglobulinemic vasculitis (CV) in patients infected with hepatitis C virus, which is most common among the "Baby Boomers" born between 1945 and 1965. Notably, a review in the New England Journal of Medicine offers specific guidance for treatment of CV at a time when the options are improving considerably. Therapy for Hepatitis C Virus–Related Cryoglobulinemic VasculitisNew England Journal of Medicine, September 12, 2013

HCV-Related Cryoglobulinemic Vasculitis
NOW@NEJM, September 13th, 2013

The authors of this review propose an algorithm for managing cryoglobulinemic vasculitis (CV), from asymptomatic to life-threatening, and review current and promising new drugs that target the hepatitis C virus (HCV) or B cells, or stimulate regulatory T cells. Even when HCV becomes undetectable after treatment, CV rarely resolves completely, although it is increasingly possible to achieve a sustained virological response with concomitant clinical improvement and reduced mortality. Dual therapy with peginterferon alfa (pIFN-α) and ribavirin (RBV) is not always successful. The addition of telaprevir or boceprevir, which inhibit HCV NS3/4A protease, increases virologic response - sometimes dramatically.

Current direct-acting agents show poorer response in the absence of pIFN-α and RBV, which are contraindicated in patients with poor renal function, greater age, and other factors associated with CV. Can pIFN-α and RBV be replaced with the new direct-acting agents? Results to date are promising but not conclusive for asunaprevir (an NS3 protease inhibitor), daclatasvir (an NS5A replication complex inhibitor), and the NS5B protease inhibitors sofosbuvir BI20712 and ABT-450.  For first-line therapy, the authors recommend pIFN-α and RBV for mild to moderate CV. But in life-threatening CV, they recommend the adding rituximab, plasmapheresis and immunosuppressive therapy.

In some patients, CV persists or relapses despite a sustained virologic response and the absence of detectable HCV RNA. Antiviral therapy would be pointless in these virus-negative patients. The alternative is glucocorticoids, then cyclophosphamide, rituximab, or other monoclonal antibodies.


Life-Threatening Cryoglobulinemic Patients With Hepatitis C: Clinical Description and Outcome of 279 PatientsMedicine, September 2013

This separate report defines the outcomes of patients with severe CV treated with the currently available options. Eighty-nine HCV-positive patients were diagnosed with cryoglobulinemic vasculitis, 30 of them life-threatening. The authors combined records of these 30 patients with results in 249 more found in a literature search. Among the total of 279 patients, 205 had renal failure, 45 had gastrointestinal vasculitis, 38 had central nervous system (CNS) involvement, 18 had pulmonary hemorrhage, and 3 had myocardial involvement. Thirty patients fell into more than one of these categories. Sixty-three of these patients (22%) died during the period of analysis. The main causes of death were sepsis (42%) in glomerulonephritis and the cryoglobulinemic vasculitis itsel,f with gastrointestinal, pulmonary, and CNS involvement (60%, 57%, and 62%, respectively).


Hepatitis C Virus Screening and Prevalence Among US Veterans in Department of Veterans Affairs CareJAMA Internal Medicine, September 9, 2013

The Centers for Disease Control and Prevention (CDC) recommends one-time HCV screening for persons born from 1945 through 1965, which includes 75% of those infected. A retrospective cohort analysis by the VA database supports this recommendation. The database contains records of 5.4 million patients, 2.9 million of whom were screened for HCV antibody or virus.HCV infection rates peaked sharply (at 18.4%)  with the cohort born in 1954, and was highest for men and blacks. Anti-HCV antibody prevalence among 2.9 million veterans was 8.4% overall, and the prevalence of HCV infection was 6.2% overall. Prevalence was 10.3% for those born during the recommended screening period (1945-1965), and markedly lower for those born earlier (1.7%) for those born or later (1.1%). Infection rates were higher among men (6.5%) than among women (2.8%), and highest for blacks (12.3%) followed by Hispanics (6.7%)

Also new last week  in the non-rheumatology journals: Two reports relating to the potential of IL-17 as a therapeutic target: Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trialLancet, online first, September 13, 2013

Comment: 17 and 23: prime numbers for ankylosing spondylitis?Lancet, online first, September 13, 2013

In a randomized, controlled trial, secukinumab rapidly reduced clinical and biological signs of active ankylosing spondylitis and was well tolerated. A phase 2 trial used Baysean methods to reduce the number in the placebo group, allowing the researchers to randomize only six patients to placebo, with 24 in the secukinumab group. After six weeks, 59% of those in the secukinumab group but only 24% of patients in the placebo group reached the primary endpoint, a 20% response on the Assessment of SpondyloArthritis International Society criteria (ASAS20). Secukinumab is a human monoclonal antibody to interleukin 17 (IL-17). Ankylosing spondylitis is associated with polymorphisms in the IL-23 receptor (IL23R) gene, including one that impairs IL-17 production by TH17 cells. IL23R polymorphisms are also found in psoriasis, in which IL-17 blockade was effective, and in Crohn’s disease, in which it was not.

Flurry of deal-making surrounds new autoimmunity targetNature Medicine, September 6, 2013

Several pharmaceutical companies are developing drugs that block the development of T helper 17 (TH17) cells in the thymus. TH17 cells produce interleukin-17 (IL-17) and other cytokines, which have a validated role in psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, asthma, and inflammatory bowel disease. The latest deal is a collaboration between Amgen and Teijin Pharma Limited to develop small-molecule drugs to block retinoic acid–related orphan receptor-gamma t (RORγt). Blocking RORγt can prevent the differentiation of TH17 cells from T-cell precursors in the thymus. So this is an upstream target that downregulates all the TH17 cytokines. Decreasing the number of TH17 cells clearly downregulated the autoimmune mechanism, but the drug developers are concerned about its effect on other tissues. Complete inhibition of RORγt can lead to opportunistic infections. GlaxoSmithKline is developing more selective ROR compounds.
 

... and this on an adverse effect of a rheumatology medication.Blurred vision: targeting a diagnosisBMJ, September 12, 2013

A 68-year-old woman with non-specific inflammatory arthritis was referred to the ophthalmologist with a three-month history of flashing lights and blurred vision. She had taken 400 mg hydroxychloroquine daily for 15 years. Visual field testing showed bilateral annular scotomas, in a characteristic “bull’s eye” appearance, which is suggestive (though not pathognomic) of hydroxychloroquine toxicity. Retinal toxicity is an established adverse effect of hydroxychloroquine, with an incidence of 0.08% to 4%. The two most important risk factors are high daily dosage (>6.5 mg/kg/day) and longer duration of treatment (>5 years). Damage apparent on ophthalmological examination is irreversible, and even after discontinuing the drug there is a risk of continued epithelial atropy. Symptoms of maculopathy (including difficulty reading and recognizing faces in a crowd as well as distorted central vision) should be referred to an ophthalmologist.