BIOLOGICAL TREATMENTS

• Last update 23 May 2010
• What
  • A family of drugs increasingly available that seem to be effective in at least some cases are monoclonal antibodies (ABs) used to treat autoimmune diseases.
    • Monoclonal refers to the process that produces identical pure antibodies.
    • Antibody refers to a protein that elicits a cellular immune system response.
  • Newer drugs are being developed to target the particular cytokines that cause the immune system malfunctions, rather than attacking a broad range of cells not involved in inflammation.
  • Mostly expensive and largely experimental
  • The earlier use of murine (mouse) derived monoclonal antibodies is giving way to humanized or fully human antibodies that are less likely to cause allergic reactions.
• Experience
  • OKT3 (Orthoclone) has been used to treat autoimmune vasculitis, but with serious side effects.  It is a murine monoclonal anti-lymphocyte antibody, which has recently been humanized and modified so it doesn't bind to Fc receptors.
  • Treatment with one murine monoclonal AB, CAMPATH-1H (Alemtuzumab, anti-CD52) used to deplete lymphocytes, has been effective both in patients with primarily cell-mediated disease, and somewhat to the researcher's surprise, it also worked very well in patients with autoantibodies, e.g. Wegener's granulomatosis.
  • At least one Australian patient reports effective treatment with Campath in the U.K., though it may have been an early version of Campath that was used in that case.
  • Campath has been approved by the FDA for use in treating B-cell chronic lymphocytic leukemia.
    • Presumably, any U.S. physician could prescribe it if she/he deems it advantageous and safe, and it might be used for  in the U.S. in the future but has not to date.
    • New biologicals have probably replaced Campath.
    • A 2005 review reported that study results demonstrated that Campath is fairly safe and 75% of the patients experienced clinical improvement and 15% of the patients were reported in clinical remission even though improvements were often transient.
    • While other biologic drugs may have narrow targets, Campath, is able to bridge the gap between immunosuppression and immuno-ablation and may offer an alternative to human stem cell transplantation avoiding the risks of chemotherapy and radiation.
    • The combination of CAMPATH-1H ("humanized Campath) followed by CD4 antibody has been able to induce remission in some patients with vasculitis that had become resistant to earlier CAMPATH as well as all conventional therapies.
  • Trials of anti-CD18 antibody (LDP-01) antibody to treat autoimmune vasculitis and in kidney transplantation have been carried out.  Some limited success treating vasculitis has been reported.
  • In the past few years, at least a number of patients with refractory vasculitis were put into remission by a combination of Prednisone or similar, and Rituximab (MabThera, an anti-CD-20 monoclonal AB used to deplete B-cells).
    • Abstract of a May 2004 article in "Current Opinion in Rheumatology" stated:  "... The success of Rituximab in a well-controlled trial confirms previous preliminary reports indicating that B cell depletion can treat established autoimmune disease."
    • There have been a few fatalities due to various causes, apparently usually due to latent infections that reactivate.
    • See more about Rituxan below.
    • Rituximab used for patients with Hepatitis C-caused cryoglobulinemia vasculitis can cause dangerous precipitations.
  • E. coli enterotoxin EtxB has been shown to be a potent immunomodulatory molecule capable of treating and preventing autoimmune disease in mice.  Further research might prove EtxB derivatives useful in treating some human autoimmune diseases.
  • A 2003 study data suggest an important role for Angiotensin Converting Enzyme (ACE) in antiatherogenic and anti-inflammatory effects. Earlier studies suggest the level of circulating Angiotensin Converting Enzyme (ACE) may track some other autoimmune vasculitis activity.
  • A 2006 study discovered that extracellular heat shock proteins (Hsp) can affect immune system activity.
  • Antibodies to Hsp might decrease or increase autoimmune inflammation.
  • There is some indication that treatment with quinine compounds might block the TLR9 receptor of B cells to prevent activating cytokines from starting the inflammation cascade.
    • The range between effective therapeutic dosage and harmful dosage of choloroquine is very narrow resulting in most quinine compound being removed from over-the-counter sale in the U.S. (and prescription use has also been largely banned perhaps with the exception of quinine sulfate for treating malaria).
    • Incorrect dosages can cause a condition where the central vision is lost.
• Current status 3Q 2007
  • PPD test
    • Persons taking long-term TNF[alpha] or others strong immunosuppressing drugs such as below, perhaps should request an annual purified protein derivative (PPD) testing to detect latent TB infection.
  • Risk of malignancy is a potential problem with the biologics, owing to their immunosuppressive properties.  The risk may be different than the risks from conventional broad immunosuppressives.
  • Anti-TNF
    • General
      • Three of the four biological medication currently available are anti-TNF (Tumor Necrosis Factor) drugs of which three have been tried with apparently some successes.
      • A limited 2006 study showed that following the failure of treatment with cyclophosphamide and high-dose corticosteroids, complete remission of SRV was observed in 2/3 of cases on anti-TNF treatment, but with adverse and in some cases, serious side-effects.
      • Anti-TNF drugs have permitted histoplasmosis infections, some fatal..
      • There's also some evidence that Adalimumab (Humira), Etanercept (Enbrel), and Infliximab (Remicade) increase the risk of various types of lymphoma, but it is difficult to determine if this is a drug effect or a reflection of the pathologic process underlying the diseases being treated.
      • In a 2007 study that only covered 3 years, anti-TNF-alpha therapy was linked to an increased risk of skin cancers. The odds ratio for developing melanoma was 2.3. Biologic use had no impact on any other type of cancer. The overall risk for all malignancies was 1.0
      • An Aug. 2008 article stated, “Treatment with TNF-alpha blocking agents did not appear to impair the immune response.
      • Recently (2008) the FDA has ordered revisions in packaging labeling warning of risks involved in Enbrel, Remicade, Humira, and Cinmzia.
    • Contraindications
      • A 2002 study suggests that continuation of antiTNF-alpha therapy should be seriously questioned if a biopsy confirms the diagnosis of leukocytoclastic vasculitis (LCV) in patients who develop skin lesions suggestive of LCV while being treated with anti-TNF therapy.
        • Other causes of LCV such as infection should be excluded, and the patient should be evaluated for possible systemic involvement, based on presenting clinical signs, tests, and symptoms.  Therapy with Prednisone or similar may be useful in causing resolution of LCV.
        • A 2007 article pointed to Group A Strep as a likely cause for cutaneous leukocytoclastic vasculitis
    • Remicade (Infliximab, Avakine)
      • Anti-TNF monoclonal antibody, in use for RA and other autoimmune diseases.
      • Contains some non-human proteins.
      • A January 2006 abstract reports that open-label clinical studies suggest a beneficial effect of Remicade in addition to standard therapy in refractory Wegener's granulomatosis.
      • A 2005 found Remicade failed to produce any improvement in patients with systemic vasculitis who were resistant to conventional immunosuppressive agents.
      • Serious adverse events, including 1 death occurred requiring termination of the study.
      • Remicade has a half-life in the body of 9.5 days.
    • Enbrel  (Etanercept)
      • Anti-TNF monoclonal antibody, in use for RA and other autoimmune diseases.
      • Aug. '04, 2005 preliminary information on the Enbrel trial indicated that Enbrel used with MTX or with Cytoxan is no more effective than MTX alone or CTX alone, and undesirable side effect may contra-indicate use for AVs.
      • Data from the first substantial reported experience of the combined use of Enbrel and cyclophosphamide, indicate that the combination of TNF inhibition with Enbrel along with cyclophosphamide may heighten the risk of cancer beyond that observed with cyclophosphamide alone.
      • Enbrel is cleared very quickly, with a half-life of 4.25 days.
    • Humira (Adalimumab)
      • Fully human anti-TNF monoclonal antibody approved for use treating RA.
      • Effective in some autoimmune conditions.
      • There has been limited use treat some AVs.
      • Limited experience suggests use of Humira and some anti-TNF alpha medications may have some association with autoimmune vasculitis, but not there's not a proven cause and effect.
      • Humira has a half-life of 14 days.
    • A newer anti-TNF, Cinzia, has been approved only for Crohn's disease.
  • Targeted biologicals
    • Rituxan (Rituximab)
      • Rituxan is a chimeric monoclonal, 60 to 65% human.
      • At least nine successful treatments reported in medical literature as of the end of 2005.
      • Rituxan is a therapeutic antibody that binds to the CD20 antigen on the surface of normal and malignant B-cells.  It then recruits the body's natural defenses to attack and kill the marked B-cells.
      • Stem cells (B-cell progenitors) in bone marrow lack the CD20 antigen, allowing healthy B-cells to regenerate after treatment and return to normal levels within several months.
      • Multiple treatments by infusion may be required.
      • Rituxan is in clinical trial at multiple locations to treat various AVs.
        See http://www.immunetolerance.org/RAVE/
        • Persons enrolled in the clinic trial get the medication at no cost.
      • Rituxan has been used either in a "Lymphoma"� protocol of four treatments of 375 mg/m²/week or an "Autoimmune"� protocol of 2 treatments of 1000 mg 14 days apart.  The RAVE trial used the lymphoma protocol.
      • Rituxan isn't risk free there have been fatalities.
        • Approximately 80% of fatal infusion reactions were associated with first infusion.
        • Some of the fatal outcomes seem to have been due mucocutaneous reactions or tumor lysis syndrome
        • Some fatal outcomes were due to reactivation of latent infections:
          • latent cytomegalovirus
          • latent visceral varicella-zoster infection
          • hepatitis B infection
          • JC polyoma virus infection which led to progressive multifocal leukoencepthalopaty (PML).
            • PML, is a rare, generally fatal demyelinating disease of the central nervous system.
            • However, PML is rare (approximately 1 in 200,000 persons). See http://www.rheumatology.org/publications/hotline/0107leuko_email_20070102.asp
            • Exposure to JC virus is endemic, with approximately 80% of healthy adults harboring latent infection.
            • Rituximab used for patients with Hepatitis C-caused cryoglobulinemia vasculitis can cause dangerous precipitations.
      • A 2006 study deduced that In Wegener's granulomatosis, granulomas tend to be less responsive to Rituxan than those without granuloma.
      • In a 2006 study, it was concluded that Rituxan when prescribed in conjunction with Corticosteroids (CS) and Immunosuppressants (IS) to treat refractory and/or relapsing WG, was able to improve clinical outcome.
        • The observed dissociation of times to response in patients with predominantly granulomatous manifestations, in contrast to vasculitis symptoms, merits further study before an optimal RTX regimen can be defined.
        • Another 2006 study showed that repeated treatment with Rituximab and prolonged B cell depletion are well-tolerated in patients with chronically relapsing Wegener's granulomatosis.
          • B cell depletion is effective at maintaining remission in these patients.
        • The use of this treatment modality for long-term remission maintenance merits further formal investigation.
      • For uses, warnings, and side effects, see http://www.rxlist.com/cgi/generic/ritux.htm
      • A Nov. 2008 review showed while rituximab is very effective in the depletion of B cells, current research suggests it may also influence other cells of the immune system by re-establishing immune homeostasis and tolerance.
      • The safety profile of RTX reveals that most reactions are infusion related. In patients with autoimmune diseases the incidence of serious and severe side effects is low. Systemic infection still remains a major concern and may result in death.
      • WARNING - Vaccinations done when B cells are depleted may not be effective.
    • Zenapax (Daclizumab)
      • Anti-IL-2, CD25 monoclonal antibody.  90% human.)
      • After the close of the NIH in-house clinical trials for autoimmune vasculitis, this research may not be continuing.
    • Abatacept (Orencia)
      • Clinical trial for phase II of Abatacept (CTLA-4 Ig) to treat ANCA positive vasculitis was scheduled to start in June 2007.
      • Click here for information on that trial and criteria for inclusion and exclusion.
    • Anti-NB1
      • A specific cell surface receptor (NB1) was discovered in 2007.  NB1 mediates the expression of a molecule (autoantigen) on the surface of certain white blood cells, where the immune system recognizes and binds it. This reaction starts the inflammation process.
      • NB1 is a potential drug target for ANCA-associated vasculitis as reported in the American journal Blood on May 15, 2007)
    • ZZe
      • (Certolizumab pegol, pegylated-antiTNF alpha).  FDA approved for Crohn's disease.  Not used for autoimmune vasculitis to date (Sept. '08)
  • Other biologicals
    • Intravenous Immunoglobulin.
      • IVGg has been found to be effective in treating some AVs, but is not often used because of expense and limited supply.
      • The University of New Hampshire and the Scripps Research Institute produced an engineered, modified IgG molecule that in the laboratory was about 30 times more effective than human IVIG in treating arthritic mice.
        • Clinical trials may be coming from Centaurus Pharmaceuticals
    • IL-32
      • IL-32 was found in 2005 to have the ability to amplify the production of certain cytokines
      • A 2006 study indicated that suppressing IL-32 might be effective in reducing inflammation-caused autoimmune disease.
    • Newer CD20 meds
      • The efficacy and success of Rituximab has led to a few other anti CD20 monoclonal antibodies being developed.
        • Ocrelizumab is a humanized ( 90 to 95% human) anti CD 20 in development.
        • Humax CD20 (Ofatumumab ) is a fully human anti CD20 in development.
        • Veltuzumab is a sub-cutaneous injection in Ph 1/2 for NHL.
      • Third generation anti CD20s have a glycoengineered Fc fragment (Fc with enhanced binding to Fc gamma receptors, which increase ADCC (antibody dependent cellular cytotoxicity.
        • Modifications in the variable regions (variable regions can enhance apoptosis of B cells.
    • LymphoStat-B
      • LymphoStat-B (belimumab) is another approach to B lymphocyte diseases that confronts their agonists and the receptors of these agonists.
      • It is a human monoclonal antibody that specifically recognizes and inhibits the biological activity of B-lymphocyte stimulator, or BLyS.
      • A large study in 2007 found that combining LymphoStat-B with conventional treatments resulted in sustained improvement in SLE (lupus).
    • Newer Biologicals
      • Experimental use of TRX4 (ToLeRx), an anti-CD3 in human and animal tests indicate it might be useful in treating autoimmune diabetes (type 1), and possibly in other autoimmune diseases.
      • Teplizumab by MacroGenics is in Phase II/III testing for use in type 1 diabetes.
      • A 2008 study at the Univ. of Alabama (Birmingham) found interleukin 17 (IL-17) causes B cells to have excessive exposure in contact with T cells in the germinal centers of lymphoid organs may allow T cells to have a greater ability to generate autoimmune antibodies.  This suggests anti-IL17 might have possible therapeutic applications in autoimmunity.
      • A 2008 study showed scientists know which HLA-G is best at down-regulating the immune response and how it works. They believe the dimmer form of the molecule's action can be augmented in people with organ transplants and autoimmune disease and turned down to help fight a tumor.
      • Another 2008 study found a protein DR3 blocks activation of T cells in mice with genetic autoimmune disease, and is potentially a therapeutic possibility.
      • Genzyme Corp's Mozobil shows it may be possible to spur bone marrow into releasing extra adult stem cells into the bloodstream.  This might provide cells that produce fewer harmful antibodies.
      • Click here to view a table of biological medications being researched or in development.

THIS SITE

• Intent
  • To assist vasculitis patients in getting early diagnoses, effective treatments, and to advise of patient, organization, and scientific resources concerning vasculitis.
• Sources Used
  • The following information is derived from a variety of sources over some ten+ years and is not to be considered as medical advice, but merely the opinions or experiences or findings of the writer who is not a physician and has no medical training.
  • Much comes from Medline abstracts and medical journal articles on vasculitis.  Some is from autoimmune vasculitis patients and carers, some from newsgroups,  internet web pages, etc. that also deal with vasculitis.
  • The compiler has attempted to use only recent valid medical information regarding vasculitis, but cannot guarantee the validity nor the currency in every case
• Limitations
  • No medical decisions should be made on the basis of information on this web page or on associated linked documents and web pages unless those are from a recognized medical professional or professional medical publication.
  • Limits to this web page concerning vasculitis:
    • The author/compiler/editor of this web page and related pages has had NO medical training.
    • Only autoimmune vasculitides will be considered, not hypersensitivity vasculitis nor vasculitis as a result of an allergic reaction to medication or vaccine..
    • Most sections apply to most autoimmune vasculitides.
      • One refers specifically to Wegener’s granulomatosis.
• Terminology
  • Some abbreviations and equivalencies are:
    • Hereafter, “autoimmune vasculitis” may be abbreviated “AV” or “AVs” for plural.
    • The term “Prednisone” is sometimes used where it or a similar glucocorticoid might be prescribed to treat vasculitis.
    • “Immunosuppressives” used to  treat vasculitis are sometimes abbreviated “ISs”.
• Updates
  • This update was on June 1, 2009 and is a complete rewrite of the former web page at http://www.wegenersgranulomatosis.net that also dealt with vasculitis.
• Files & links – Vasculitis related.
  • Click here to view a web page listing all the links and files from this page.
• Tables & Figures – Vasculitis related
  • Click here to view a listing of the tables and figures in this web page.
• Disclaimer
  • ALL MEDICAL QUESTIONS, SYMPTOMS, CONCERNS AND PROBLEMS SHOULD BE DIRECTED TO APROPRIATE LICENSED MEDICAL PROFESSIONALS.
  • The writer/editor/compiler does not vouch for the accuracy, completeness, nor applicability of the information included on this site to any person, whether a vasculitis patient or otherwise. 

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