Primary Immunodeficiency and Biologic Therapies

IFN-α has a direct antiviral effect through induction of antiviral proteins and has been used most commonly for the treatment of hepatitis B, hepatitis C and human papilloma virus (HPV).  It was originally approved by the FDA in 1986 for treatment of hepatitis C.  This biologic has also been utilized for treatment of patients with primary immunodeficiency.

 

IFN-α therapy has been used to successfully treat viral infections in patients with Hyper IgE syndrome (HIES). A 9 year old boy with HIES, severe eczema and intractable molluscum contagiosum was treated with IFN-α for a 6 month period with marked improvement of his lesions [1].  Similarly, an 11 year old boy with DOCK8 deficiency with persistent warts was treated with IFN-α with significant improvement in symptoms.  This patient had reduced plasmacytoid dendritic cells in circulation and profound lack of IFN-α production upon stimulation of PBMCs with CpG indicating a relative deficiency of IFN-α in this disease [2].

 

A Japanese patient with X-linked agammaglobulinemia with encephalitis (presenting as mental deterioration and gait abnormalities) was empirically treated with high dose IVIG and IFN-α for 6 weeks.  While the exact etiology of the encephalitis was ultimately not identified, the patient had symptom improvement within 1 month of starting therapy [3].

 

A patient with idiopathic CD4 lymphocytopenia with disseminated giant molluscum contagiosum (which was resistant to imiquimod therapy) was treated with IFN-α for 16 months.  The molluscum lesions resolved completely and no recurrence was reported over 4 years [4].

 

Patients with mutations in the TLR3 pathway (TLR3, UNC-93B, TBK1, TRAF3, TRIF, IRF3) have a unique susceptibility to recurrent herpes simplex encephalitis (HSE) due to impaired neuronal (but not leukocyte) production of IFN-α.  The susceptibility of neurons to HSV could be corrected in vitro with administration of IFNα or IFNβ suggesting this therapy could potentially benefit patients with TLR3 pathway defects suffering from HSE [5].

The most common use of IFN-γ therapy for primary immunodeficiency has been for patients with chronic granulomatous disease (CGD).  In a double-blind randomized placebo-controlled trial of IFN-γ therapy in 128 CGD patients, the frequency of serious infections decreased by 70% in both X-linked and autosomal recessive CGD [6]. This is now an FDA approved maintenance therapy for patients with CGD to reduce frequency of infections.  While earlier in vitro data suggested increased superoxide production occurred when macrophages were stimulated with IFN-γ, follow up studies indicated that the clinical benefit of this therapy was not accompanied by improvement in NADPH oxidase function [7, 8].

 

IFN-γ is required for the killing of intracellular pathogens and this therapy has been used to successfully treat patients with IL-12Rβ1 deficiency with non-tuberculous mycobacteria or Salmonella infections [9-11].  IFN-γ has also been used to treat disseminated Mycobacterium avium infection in a 20 year old patient with partial IFN-γR1 deficiency [12].

 

IFN-γ therapy has previously been used to treat a patient with X-linked SCID suffering from disseminated Mycobacterium bovis infection to help control the infection allowing the patient to proceed to bone marrow transplantation without rejection [13].

 

IL-2 is a T cell stimulatory cytokine that is also able to potently activate NK cells.  High dose IL-2 therapy is currently FDA approved for the treatment of malignant melanoma and renal cell carcinoma.  

 

Use of low dose IL-2 therapy has been studied in patients with Wiskott-Aldrich syndrome (WAS).  Patients with WAS suffer from recurrent herpes virus infections and malignancy attributed to reduced NK cell function.  WAS protein (WASp) facilitates filamentous actin (F-actin) branching and is required for NK cell immunological synapse formation and NK cell cytotoxicity.  Exogenous application of IL-2 to WAS NK cells can restore defective NK cell function through activation of the WASp homolog WAVE2 which in turn can facilitate F-actin organization [14].  In a phase I clinical trial of WAS patients treated with low dose IL-2 (0.5MU/m² for 5 days every 2 months), improvements in lymphocyte counts, platelets and T regulatory cell (Treg) numbers were observed.

 

T regs are highly responsive to IL-2 and the use of low dose IL-2therapy has been reported to expand Tregs in vivo and improve a number of autoimmune conditions including lupus, type 1 diabetes, alopecia areata and hepatitis C virus induced vasculitis [15-19].  Ultra-low dose IL-2 (100,000 – 200,000 IU/m² x 3 per week) has also been reported to be clinically effective in preventing GVHD and viral infections in patients post-HSCT [20].

 

IL-2 therapy has also been studied in patients with common variable immunodeficiency (CVID).   Cunningham-Rundles et al. reported decreased number of days of bronchitis, diarrhea or joint pain in 15 patients with CVID who received low dose IL-2 therapy for 12-18 months (T cell function and antibody production were enhanced in treated patients) [21].  In a double-blind, placebo controlled, crossover study with 10 CVID subjects, Rump et al. showed reduced susceptibility to severe infections in the 6 months following treatment [22].

 

A small number of patients with idiopathic CD4 lymphopenia (ICL) have been treated with IL-2 therapy.  In an ICL patient with mycobacterium avium intracellulare lung infection, long term IL-2 therapy was well-tolerated and resulted in complete resolution of disease without recurrence [23].  In a second patient suffering from cryptococcal meningitis refractory to antifungal therapy, IL-2 therapy led to complete resolution of the infection and a rise in the CD4 T cell count [24].  A patient with ICL and chronic progressive CMV retinitis despite anti-CMV therapy had cure of disease following IL-2 therapy [25].

Regent et al. previously reported 4 of 6 patients with ICL had increased CD4 T cell counts with IL-2 treatment [26].

 

Finally, in a single patient with NEMO deficiency treated with IL-2 over a 6 month period, improved NK cell cytotoxicity was observed [23].

 

Rituximab therapy results in rapid depletion of B cells resulting in reduction of autoantibody production.  This therapy has been quite effective in the management of CVID associated autoimmune manifestations such as ITP and hemolytic anemia [27].  Rituximab has also been useful for management of autoimmune complications and lymphadenopathy in hyper IgM syndrome and refractory autoimmune cytopenias in autoimmune lymphoproliferative syndrome (ALPS) [28, 29].  

 

Granulomatous interstitial lung disease (GLILD) is a restrictive lung disease that can occur in patients with CVID that is associated with early mortality.  Patients with GLILD who received combination therapy with rituximab ((375 mg/M2 once weekly x 4 weeks) every 4-6 months and daily azathioprine (1.0–2.0 mg/kg/day, 18 months duration) had marked improvement in lung function and decreased radiographic findings without any significant medication related side effects [30].

 

Epstein-Barr virus (EBV)-associated B-cell lymphoproliferation is a serious complication after hematopoietic stem cell transplantation resulting from expansion of EBV-infected B cells that would normally be controlled by EBV-specific cytotoxic T cells.  Rituximab is used for both prophylaxis and treatment of EBV driven post-transplant lymphoproliferative disease [31].

 

EBV lymphoproliferation is also a life-threatening clinical manifestation of certain primary immunodeficiencies.  Rituximab has been used effectively to treat primary EBV infection in X-linked lymphoproliferative disease (XLP1) as well as EBV lymphoproliferation in a patient with NF-κB1 haploinsufficiency with rapid induction of remission [32, 33].

 

Patients who develop interferon gamma (IFN-γ) autoantibodies have impaired IFN-γ immune response and increased susceptibility to intracellular pathogens (especially non-tuberculous mycobacteria).  In these patients, rituximab therapy has been shown to reduce IFN-γ autoantibody levels and improve IFN-γ signaling allowing for clearance of infection [34].

 

IL-1 is a key inflammatory cytokine that mediates the body’s fever response.  Pro IL-1 is cleaved to form IL-1 by the NLRP3 inflammasome.  Cryopyrin-associated periodic syndromes (CAPS) are caused by gain of function mutations in NLRP3 that results in excess IL1β production.  Anakinra (a short acting IL1 recptor antagonist), canakinumab (a Q8 week fully humanized anti-IL1β monoclonal antibody) and rilonacept (a recombinant soluble IL1 receptor given once weekly) have been approved for treatment of patients with CAPS.  

 

Anti-IL-1 therapies have also been useful in cases of familial Mediterranean fever (FMF) refractory to colchicine therapy, hyper IgD syndrome (mevalonate kinase deficiency), pyogenic arthritis pustulosis acne (PAPA) syndrome, and Tumor Necrosis Factor Receptor Associated Periodic Syndrome (TRAPS), and deficiency of IL-1 receptor antagonist (DIRA) [35, 36].

 

Previously, in vivo studies in p47 phoxˉˊˉ CGD mice have shown that defects in autophagy due to reduced reactive oxygen species production result in increased release of IL-1β.  Anakinra therapy resulted in reduced secretion of IL-1β and restoration of autophagy, colitis and protection from invasive aspergillus [37].

 

While early reports in 2 patients with CGD colitis treated with Anakinra for 3 months showed improvement in clinical symptoms, a susequent report by Hahn et al. of 5 CGD patients treated with Anakinra revealed minimal sustained improvement [37, 38].

 

STAT3 gain of function (GOF) mutations are associated with early onset autoimmunity (ITP, hemolytic anemia, enteropathy, lymphocytic interstitial pneumonia, hepatitis, scleroderma, and type I diabetes), marked short stature and hypogammaglobulinemia.  STAT3 GOF results in reduced STAT5 and STAT1 phosphorylation and reduced Treg numbers [39]..  

 

IL-6 is a key cytokine that activates the STAT3 signaling pathway.  Tocilizumab is an anti-IL-6R monoclonal antibody which can inhibit downstream STAT3 transcriptional activity and has been shown to improve the autoimmune manifestations in STAT3 GOF.  In one patient who received this therapy, there was significant improvement in joint contractures related to polyarthritis [39].  Another patient had marked improvement of autoimmune enteropathy following tocilizumab therapy and was found to have a concurrent increase in Treg levels [40].

 

CTLA4 is a protein expressed on activated T cells and Tregs that inhibits immune responses by negative signaling and competes with the co-stimulatory signaling molecule CD28 for CD80/86 binding.  Reduced CTLA4 results in increased autoimmunity due to diminished Treg suppressive activity.  

 

CTLA-4 deficiency is an autosomal dominant disease characterized by a CVID phenotype and severe autoimmunity.  Patients develop multi-organ autoimmune manifestations including autoimmune cytopenia, inflammatory bowel disease, psoriasis, and thyroid disease. Patients also develop splenomegaly, hepatomegaly, bronchiectasis, GLILD, and generalized lymphadenopathy.  Abatacept is a fusion protein created by combining the Fc domain of IgG1 to the extracellular domain of CTLA4 which can restore the negative signaling through CD80/86 to suppress autoimmunity.  Lee et al. reported the clinical efficacy of abatacpt in a patient with CTLA4 deficiency who suffered from autoimmune enteropathy, autoimmune hepatitis and megaloblastic anemia.   Abatacept therapy was able to greatly reduce the autoimmune disease manifestations and restored Treg functionality [41].

 

LRBA deficiency is an autosomal recessive disease that mirrors the clinical phenotype of CTLA4 deficiency with CVID and severe autoimmunity (LRBA plays a role in lysosomal turnover of CTLA4 and thus surface expression of CTLA4).  Lo et al. demonstrated the efficacy of abatacept in 3 patients with LRBA deficiency with significant improvement in interstitial lung disease, autoimmune cytopenias, autoimmune hepatitis, and uveitis [42].

 

STAT1 gain of function (GOF) mutations are associated with a variable primary immunodeficiency characterized by chronic mucocutaneous candidiasis (CMCC), invasive fungal infections, hypogammaglobulinemia, impaired vaccine responses, and autoimmune disease (enteropathy, ITP, hemolytic anemia, alopecia areata).  Increased phosphorylation of STAT1 results in enhanced Th1 cell responses but suppression of Th17 immunity.  

 

Ruxolitinib is an oral JAK 1/2 inhibitor that shows great promise in treating the autoimmune and infectious manifestations in patients with STAT1 GOF.  In a patient with treated with ruxolitinib (20mg twice daily), there was marked improvement of alopecia areata (with full hair regrowth) and CMCC symptoms [43].  In another patient, ruxolitinib therapy (10 mg/m²/day divided BID) resulted in remission of refractory autoimmune cytopenias (ITP and hemolytic anemia) and improvement in CMCC.  CD4 T cells from this patient demonstrated both normalization of enhanced interferon gamma production and increased IL-17 production [44].  However, Zimmerman et al. also described 2 patients with STAT1 GOF who failed to have any improvement in severe fungal infections (coccidiomycosis and dermatophytosis) on this therapy.  Ruxolitinib treatment also had a negative in vitro effect on IL-17 secretion from PBMCs of both patients (one patient did not have increased Th17 number or IL-17 secretion after two weeks of therapy) [45].

 

The mammalian target of rapamycin (mTOR) plays a critical role in T cell proliferation.  Rapamycin (sirolimus) is an mTOR inhibitor which has been used to treat patients with immune dysregulation.

Rapamycin has been effective in the treatment of autoimmune enteropathy in IPEX syndrome.  The efficacy of this medication is likely due to its ability to reduce T effector cell proliferation while maintaining Treg cells [46, 47].

Activating mutations in PIK3CD result in an autosomal dominant syndrome characterized by a CVID phenotype (low IgG and IgA but elevated IgM with impaired vaccine responses), reduced naïve T cells, autoimmunity, and malignancies.  Patients have enhanced activation of the mTOR pathway resulting in proliferation and terminal differentiation of T cells that have impaired function.  Lucas et al. reported clinical improvement and normalization of the depleted naïve T cell compartment of patients treated with rapamcin [48].

 

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