NON-SPECIFIC IMMUNE ACTIVATION

Molecular Evidence (rationale) for non-specific immune activation therapy in iMCD patients:

“Many of the immunosuppressive actions of glucocorticoids are mediated by interference with signaling by the key inflammatory transcriptional regulators; NF-κB” (Coutinho and Chapman)

Case Reports of non-specific immune activation therapy for iMCD patients:

Corticosteroid monotherapy. Corticosteroids can improve symptoms during acute exacerbations of iMCD, but most patients relapse during steroid tapering. Fourteen iMCD patients achieved complete remission in response to corticosteroid monotherapy and one patient achieved complete remission from steroids and plasma exchange. Twenty-seven iMCD patients achieved partial remission. Eleven iMCD patients achieved no response, five patients got worse as a result of corticosteroid monotherapy and one patient achieved no response to corticosteroids, IVIG and blood transfusions. Please see patient descriptions below.

25-year-old male with iMCD-TAFRO received 1st-line corticosteroid monotherapy for partial response for 2 months and then the patient relapsed. 2nd-line rituximab achieved partial response for 2 months and then the patient relapsed. 3rd-line siltuximab, corticosteroids, rituximab, IVIG, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin + cyclophosphamide + etoposide) and maintenance therapy of thalidomide, bortezomib, dexamethasone, rituximab (for 3 months) and ongoing siltuximab achieved a complete remission for 15 months and then the patient relapsed. 4th-line rituximab, tocilizumab, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin + cyclophosphamide + etoposide) with maintenance therapy of thalidomide (daily), bortezomib (weekly), dexamethasone (weekly), and siltuximab (every 3 weeks) for full response and then relapsed at 17 months. 5th-line rituximab, cyclosporine, IVIG, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin + cyclophosphamide + etoposide) with maintenance therapy of IVIG and sirolimus with complete response for 39 months. (Patient reported in Fajgenbaum et al with subsequent data collected)
40-year-old male with hyaline-vascular iMCD and membranoproliferative glomerulonephritis treated with 6 months of corticosteroids (prednisone) with no response (improved edema, early low-grade fever, hyperglobulinemia, urinalysis, but persistent anemia and renal function changes). 2nd line therapy was CVP chemotherapy for 3 times in the next 3 months with resolution of anemia and and renal function. Third-line was splenectomy and regional retropeitoneal lymphadenectomy with no response for 44 months. (Zhang et al)
71-year-old male with hepatic amyloidosis and mixed-type iMCD received 1 month corticosteroid monotherapy without response, then died of unrelated cause. Patient had previously received cyclophosphamide plus prednisolone without response for 2 month period of treatment. (Gianstefani et al)
48-year-old male of Mediterranean origin with plasma-cell variant iMCD with irreversible kidney damage received first-line high dose steroids without response. 2nd-line therapy included R-CHOP for partial response for 12 months, patient’s general condition improved with serum albumin and systolic blood pressure normalized. After second course, the patient’s condition was complicated by pneumonia and multiorgan system failure. (Kahn et al)
48-year-old female with iMCD treated with corticosteroids with partial response (Hyperimmunoglobulinemia and lymphadenopathy were moderately sensitive) for 132 months then relapsed. 2nd-line cyclophosphamide plus corticosteroids was not associated with improved response and was poorly tolerated. 3rd-line 6 cycles of bortezomib with IL-6 level reduced and general performance status improved. (Kreft et al)
73-year-old male with mixed-type iMCD and concomitant diffuse large B cell lymphoma received first-line prednisone with partial remission for 4 months then relapsed (lower extremity edema, fever and weakness, anemia, remarkable lymphadenopathy of the chest, hypocalcemia, renal failure). Patient then received 2nd-line CHOP with no response for 6 months. Patient passed away at 6 months after diagnosis of lymphoma from complication of pneumonia and sepsis. (Venizelos et al)
24-year-old female with a history of connective tissue diseases and mixed-type iMCD received daily pulses of IV methylprednisolone followed by high dose steroids for less than 1 month with no response (got worse). Patient then received 2nd-line CHOP + Azathioprine maintenance with partial remission for 25 months without documented relapse. (De Marchi et al)
55-year-old male with iMCD, presumed TAFRO, associated with Acute Myelogenous Leukemia M5b received prednisolone monotherapy with partial response (pancytopenia, skin rash, and cervical lymph node enlargement subsequently resolved) for 27 months then relapsed. Patient then received 2nd-line cytotoxic chemotherapies (cytarabine, etoposide, and mitoxantrone) without response. Patient subsequently developed invasive pulmonary aspergillosis and received amphotericin B from day 12 after chemotherapy, developed massive pulmonary hemorrhage that resulted in his death from respiratory failure on day 76 after chemotherapy. (Tomonari et al)
53-year-old female with plasmacytic-type iMCD received oral prednisolone monotherapy (60 mg/day tapering to 25 mg/day by 4 months, then maintained at 25mg/day) with partial response (symptoms disappeared, improvement in elevated levels of CRP, IL6, IL2R, and LDP) for 5 months, then relapsed. Patient then received second-line methyl-prednisolone pulse therapy (1 g/day for 3 days) and followed by oral prednisolone (25 mg/day) and cyclophosphamide (CPA at 100 mg/day) with partial response for 48 months without relapse. (Iyongaga et al)
57-year-old female with iMCD-TAFRO treated with corticosteroids (pulse therapy of methylprednisolone and prednisolone) for less than 1 month with worsening condition. 2nd-line therapy was corticosteroids (methylprednisolone) and cytotoxic chemotherapies (CHEOP) with transient improvement then death secondary to septic shock. (Masaki et al)
7-year-old male with plasmacytic-type iMCD received 1st-line methylprednisolone monotherapy with partial response for 9 months then relapsed when treatment was discontinued and again as 3rd-line methylprednisolone monotherapy with partial response for 18 months without relapse. First-line therapy was methylprednisolone pulse therapy with partial response for 9 months, but relapsed with similar clinical and laboratory symptoms within a few days of discontinuing steroids preoperatively. 2nd-line therapy of four courses of cytotoxic chemotherapies (CHOP) + corticosteroids (prednisolone) was administered without response and relapse 3 months later. Patient then resumed high-dose pulse methylprednisolone treatment, tapered dose in a month and continued with partial response for 18 months without relapse. (Karapinar et al)
74-year-old man with plasma cell type iMCD was treated with prednisone monotherapy for 21 months with complete response (90% regression based on imaging reports), but died 21 months later due to septic shock (when hospitalized for knee arthritis). (Khalil et al)
78-year-old female with a 17-year history of sarcoidosis and mixed-type iMCD was unresponsive to first line corticosteroids (did not control DIC, ascites, pleural effusion), achieved complete remission for 32 months on 2nd-line treatment tocilizumab, after which she died suddenly due to unknown cause. (Awano et al)
58-year-old female with hyaline-vascular-type iMCD received high dose corticosteroids with partial remission for 2 months (remission of abdominal symptoms, confirmed partial regression of lesions), however a rapid progressive mechanic jaundice associated with liver failure arose three months after initial diagnosis, with 5 by 6.5 cm lesion at the hepatic hilus, and patient died of multiorgan failure. (Mura et al)
67-year-old male with a history of labile hypertension, viral hepatitis, remote myocardial infarction with plasmacytic-type iMCD who received prednisolone monotherapy with partial remission for 6 months (partial resolution of skin lesions, complete regression of lymphadenopathy), but relapsed. Second-line therapy was 8 cycles of prednisolone, cyclophosphamide, doxorubicin, vinblastine that resulted in complete remission for 52 months (a nearly complete clearing of skin lesions with postinflammatory hyperpigmentation), when he died of gastric carcinoma. (Haque et al)
A previously well, 41-year-old Chinese male with iMCD treated with corticosteroids with complete remission for 24 months (endoscopic and hematologic evidence of resolution of the obstruction), without known relapse. (Heng et al)
25-year-old female with hypercalcemia associated with iMCD was treated with high dose corticosteroids with partial response (diminished conjunctival injection, joint swelling, and pain) for 8 months, then relapsed. 2nd-line treatment of dexamethasone plus rituximab with complete response (good control of her eye and joint symptoms) for 10 months without relapse. (Washington et al)
47-year-old female with iMCD with abundant IgG4-positive cells who was treated with corticosteroid monotherapy with partial remission for 26 months with worsening of symptoms on reduced dose of steroid, but without relapse. (Sato et al)
50-year-old male with iMCD with abundant IgG4-positive cells who received corticosteroid monotherapy with complete remission (disappearance of lymph node swelling and multiple lung nodules, negative test results for autoantibodies) for 31 months without relapse. (Sato et al)
43-year-old female with a history of idiopathic thrombocytic purpura, Sjogren’s syndrome, systemic sclerosis and mixed-type iMCD, presumed TAFRO, received Prednisone (50mg/day) and achieved complete remission without relapse for 186 months.(Koijima et al)
51-year-old female with a history of Sjogren’s syndrome with mixed-type iMCD who received Prednisone (250mg/day) and achieved complete remission for 35 months without relapse. (Koijima et al)
52-year-old female with a history of idiopathic thrombocytic purpura with hyaline-vascular type iMCD, presumed TAFRO, who received Prednisone (250mg/day) and achieved complete remission for 75 months without relapse. (Koijima et al)
53-year-old female with a history of idiopathic thrombocytic purpura with mixed-type iMCD, presumed TAFRO, who received Prednisone (30mg/day) and achieved complete remission for 29 months without relapse. (Koijima et al)
55-year-old male with a history of idiopathic thrombocytic purpura with mixed-type iMCD, presumed TAFRO, who received Prednisone (60mg/day) and achieved complete remission for 87 months without relapse. (Koijima et al)
68-year-old male with plasmacytic-type iMCD, presumed TAFRO, who received prednisone and achieved complete remission for 3 months without relapse. (Koijima et al)
17-year-old female with a history of depression, treated left renal artery stenosis secondary to fibromuscular dysplasia and mixed variant iMCD who received prednisone for 1 month without response (continued to have ongoing symptoms, lymphadenopathy, splenomegaly, and thrombocytopenia). Patient achieved complete remission for 31 months without relapse on rituximab. (Mian et al)
21-year-old male with a history of primary immunodeficiency (common variable immunodeficiency) and iMCD who received IV and PO steroids without response for 18 months. 2nd-line monthly IVIg (with bactrim prophylaxis for CD4 lymphopenia) with partial response (overall clinically stable) for 45 months. Patient died of severe pulmonary infection, sepsis and respiratory failure. (Drolet et al)
67-year-old male with IgG4-related lung disease associated with iMCD and squamous cell carcinoma of the lung was treated with corticosteroids with partial response. Patient was then followed clinically without further treatment until he presented with an acute pulmonary exacerbation 15 months after surgery, patient died secondary to complications of disease recurrence. (Ikari et al)
61-year-old female with iMCD received repeated courses of steroid monotherapy without response. Patient previously achieved partial remission (improved blood counts, lymphadenopathy resolved, but intermittent fever and rash persisted) for 36 months while on first-line siltuximab. 2nd-line treatment at 36 months included corticosteroids plus etanercept with no response. 3rd-line consecutive plateletpheresis for thrombocytosis and then cladribine for 5 days with no response. Patient was then treated with repeated courses of steroids, and later was started on naprosyn for possible neoplastic fever. She also received a weekly dose of rituximab for 8 weeks, with persistence of disease flare up. Patient achieved a complete remission of 7 months on 5th-line anakinra. (El-Osta et al)
70-year-old male with Parkinson disease and plasma cell-type iMCD involving the orbital areas was treated with corticosteroid monotherapy with marked clinical and laboratory improvement for 6 months without recorded relapse. (Venizelos et al)
25-year-old male with iMCD, presumed TAFRO, was treated with prednisone with partial remission for 42 months, no relapse documented (Koijima et al)
41-year-old female with 4-year history of bone marrow plasmacytosis in idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia, presumed TAFRO, was treated with prednisone monotherapy with partial remission for 24 months, no relapse. (Koijima et al)
52-year-old male with bone marrow plasmacytosis in idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia treated with prednisone alone and achieved partial response for 120 months, then died of renal failure. (Koijima et al)
50-year-old male with hyaline-vascular variant iMCD treated with corticosteroid monotherapy with improved liver function, partial remission for unknown number of months. (Park et al)
37-year-old Japanese female with iMCD was initially treated with corticosteroid monotherapy with partial response for 5 months, then relapsed. 2nd-line therapy of Tocilizumab achieved partial response for 4 months without relapse (alleviated generalized fatigue, pyrexia, and biochemical abnormalities, including anemia, hypoalbuminemia, hypergammaglobulinemia, and increased C-reactive protein), but was ultimately discontinued due to concern for DIC. (Matsuyama et al)
Female patient with iMCD, complicated by cardiomyopathy and congestive heart failure, was unresponsive to first-line treatment with corticosteroid monotherapy for 36 months. Patient achieved partial response to tocilizumab for 2 months without documented relapse for period of follow-up. (Kanda et al)
42-year-old female with a history of basal cell carcinoma and iMCD treated with corticosteroids and hydroxyurea with partial response for 60 months, but died 5 years after diagnosis from aspiration pneumonia. (Kreft et al)
48-year-old female with iMCD treated with corticosteroid monotherapy with partial response (Hyperimmunoglobulinemia and lymphadenopathy were moderately sensitive) for 132 months, then patient relapsed. 2nd-line corticosteroids plus cyclophosphamide was not associated with improved response and was poorly tolerated. 3rd-line was 6 cycles of bortezomib with IL6 level reduced and general performance status improved. (Kreft et al)
71-year-old male with plasmacytic-type iMCD received corticosteroid monotherapy with partial response for 6 months (skin lesions disappeared, although residual pigmentation remained, anemia and hypoalbuminaemia corrected, CRP and serum gammaglobulin concentrations decreased). (Kayusut et al)
26-year-old previously healthy female with iMCD treated with prednisolone monotherapy for maintenance without evidence of disease for 82 months. 1st-line therapy of methylprednisolone plus rituximab achieved complete response for 16 months. After rituximab administration, fever remarkably improved, pleural effusion, ascites, and generalized lymphadenopathy disappeared. CRP, IgG, IL-6 and soluble IL-2 levels normalized. Patient stopped rituximab due to pregnancy. Patient’s baby was healthy and patient had no sign of recurrence of MCD after pregnancy. She was started on oral prednisolone for maintenance therapy. Follow-up at 82 months, patient was alive with no evidence of disease. (Ide et al)
52-year-old female with hyaline-vascular iMCD treated with predonine monotherapy with partial response for 12 months without reported relapse.(Koijima et al)
55-year-old male with mixed-type iMCD treated with prednisolone monotherapy with partial remission for 21 months without reported relapse. (Koijima et al)
73-year-old male with mixed-type iMCD and concomitant diffuse large B cell lymphoma in the neck received prednisone monotherapy with partial remission for 4 months then readmitted with lower extremity edema, fever and weakness, anemia, remarkable lymphadenopathy of the chest, hypocalcemia, renal failure. Patient received 2nd-line CHOP with no response for 6 months. Patient passed away at 6 months after diagnosis of lymphoma from complication of pneumonia and sepsis. (Venizelos et al)
24-year-old female with a history of connective tissue diseases and mixed-type iMCD received daily pulses of IV methylprednisolone followed by high dose steroids for less than 1 month with no response (got worse). Patient then received 2nd-line CHOP plus azothioprine maintenance with partial remission for 25 months without documented relapse. (De Marchi et al)
79-year-old female with hypertension, hypercholesterolemia, status-post cholecystectomy with iMCD, presumed TAFRO, treated with prednisolone monotherapy with partial response for 1 month (anaemia, proteinuria and haematuria resolved, persistent thrombopenia treated with Danazol). (Karie et al)
52-year-old Japanese male with hyaline-vascular-type iMCD, presumed TAFRO, associated with glomerular microangiopathy and MPGN-like lesion treated with prednisolone with partial remission for 12 months (fever regressed, and lymphadenopathy, generalized edema, and anemia, abated. CRP, VEGF, and IL-6 concentrations completely normalized within a month) with no relapse recorded. (Seida et al)
55-year-old male with iMCD, presumed TAFRO, associated with Acute Myelogenous Leukemia M5b received prednisolone monotherapy (50 mg/day then gradually tapered) with partial response (pancytopenia, skin rash, and cervical lymph node enlargement subsequently resolved) for 27 months then relapsed. 2nd line cytotoxic chemotherapies (cytarabine, etoposide, and mitoxantrone) without response. Patient subsequently developed invasive pulmonary aspergillosis and received amphotericin B from day 12 after chemotherapy, developed massive pulmonary hemorrhage that resulted in his death from respiratory failure on day 76 after chemotherapy. (Tomonari et al)
37-year-old male with a history of autoimmune hemolytic anemia and plasma-type iMCD treated with prednisolone monotherapy with partial response (rapidly improving symptoms and diminished swelling of LN, but remained enlarged) for 3 months without relapse. (Ishii et al)
48-year-old Japanese female with iMCD treated with corticosteroid monotherapy with no response. (Yamasaki et al)
6-year-old female with hyaline-vascular iMCD, presumed TAFRO, received corticosteroid monotherapy with complete remission for 16 months without relapse. (Smir et al)
6-year-old female with plasmacytic-type iMCD, presumed TAFRO, treated with splenectomy plus corticosteroids with complete response the relapse 5 months after, which was controlled with steroids with complete remission for 74 months without relapse since paper was published. (Smir et al)
57-year-old female with iMCD-TAFRO, treated with corticosteroids (pulse therapy of methylprednisolone and prednisolone) for less than 1 month with worsening condition. 2nd-line therapy was corticosteroids (methylprednisolone) and cytotoxic chemotherapies (CHEOP) with transient improvement then death secondary to septic shock. (Masaki et al)
73-year-old male with a history of aplastic anemia, diabetes mellitus, hypothyroidism, chronic heart failure with mixed-type iMCD-TAFRO with associated neurinoma who received prednisolone monotherapy with partial response (hyperinflammation including CRP, IgG, IgG4 and IL6 improved) for 1 month and no subsequent relapse. Open brain surgery performed for brain tumor then general condition, including pleural effusion and ascites, worsened and CRP and IL6 increased markedly. The patient died secondary to multiorgan system failure. (Masaki et al)
49-year-old female status-post caesarean section with iMCD-TAFRO who was treated with corticosteroid (dexamethasone, prednisolone) with full resolution of symptoms with partial response for 1 month, no subsequent relapse. On the 36th day, patient was treated with cyclosporin A (5 mg/kg) with complete remission for 1 month without relapse. Prednisolone was stopped on the 53rd day after tapering. (Inoue et al)
33-year-old man with plasmacytic-type iMCD, presumed TAFRO, with crescentic glomerulonephritis treated with corticosteroid plus plasma exchange with complete remission (anti-GBM antibodies normalized by 2 weeks and indirect Coombs test became negative, lymphadenopathy, splenomegaly, generalized edema, anemia, thrombocytopenia, and anemia resolved) for 6 months then relapsed. Relapse was treated with COP chemotherapy every month, with partial response for 20 months then restarted another course of chemotherapy. (Lv et al)
50-year-old male with autoimmune hemolytic anemia and iMCD received corticosteroids (prednisolone), IVIG and blood transfusions with no response for 10 days. Patient then received 2nd-line R-CHOP with complete remission for unknown period of time and passed away from accident without relapse of CD. (Tajima et al)

IVIG (Intravenous Immunoglobulin G). Two iMCD patients received IVIG monotherapy, one achieved partial response and the other achieved no response. IVIG in combination with other drugs was used to treat four iMCD patients. Three out of four patients achieved no response, while one iMCD-TAFRO patient achieved complete remission. Please see patient descriptions below.

21-year-old male with a history of primary immunodeficiency (common variable immunodeficiency) and iMCD received 2nd-line monthly IVIG (with bactrim prophylaxis for CD4 lymphopenia) with partial response (overall clinically stable) for 45 months, then died of severe pulmonary infection, sepsis and respiratory failure. 1st-line therapy was IV and PO steroids without response for 18 months. (Drolet et al)
7-year-old female with iMCD was initially treated with infusions of immunoglobulins with no response. Patient achieved partial response on tocilizumab for 8 months without relapse. (Galeotti et al)
4-year-old girl with mixed-type iMCD, presumed TAFRO, was treated with IVIG, cytotoxic chemotherapies (CVD), prednisone for four cycles with no response. 2nd-line treated with cyclophosphamide, vincristine, doxorubicin, and prednisone with partial remission for 36 months. Follow-up imaging at 30 months after completion of chemotherapy showed marked improvement in soft tissue swelling and ascites with small residual lymph nodes present without new large lymph masses. All laboratory abnormalities (anemia, thrombocytopenia, hypoalbuminemia, C-reactive protein, and renal function) normalized after starting chemotherapy. Patient was free of disease at 36 months of follow-up. (Baserga et al)
61-year-old female with hyaline-vascular type-iMCD status-post splenectomy for iMCD treatment received IVIG, rituximab and daily steroids with no response and died secondary to paraneoplastic pemphigus. Patient initially presented with nearly-fatal myocarditis associated with a 2009 pandemic H1N1 influenza virus infection. 1st-line cytotoxic chemotherapy with no response for 2 months. 2nd-line included antibiotics, oseltamivir, furosemide, and spironolactone with improvement of all clinical parameters. Three years later, 3rd-line treatment IVIG and rituximab and daily steroids with no response and deterioration in condition, patient died of paraneoplastic pemphigus. (Roca et al)
25-year-old male with iMCD-TAFRO received IVIG in combination with other drugs with complete remission for 15 months then relapsed and complete remission for 39 months without relapse. 1st-line corticosteroid monotherapy for partial response for 2 months and then the patient relapsed. 2nd-line rituximab achieved partial response for 2 months and then the patient relapsed. 3rd-line siltuximab, corticosteroids, rituximab, IVIG, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin + cyclophosphamide + etoposide) and maintenance therapy of thalidomide, bortezomib, dexamethasone, rituximab (for 3 months) and ongoing siltuximab achieved a complete remission for 15 months and then the patient relapsed. 4th-line rituximab, tocilizumab, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin + cyclophosphamide + etoposide) with maintenance therapy of thalidomide (daily), bortezomib (weekly), dexamethasone (weekly), and siltuximab (every 3 weeks) for full response and then relapsed at 17 months. 5th-line rituximab, cyclosporine, IVIG, cytotoxic chemotherapies (velcade-methylprednisolone-thalidomide-adriamycin + cyclophosphamide + etoposide) with maintenance therapy of IVIG and sirolimus with complete response for 39 months. (Patient reported in Fajgenbaum et al with subsequent data collected)
50-year-old male with autoimmune hemolytic anemia and iMCD received IVIG, corticosteroids (prednisolone) and blood transfusions with no response for 10 days. Patient then received 2nd-line R-CHOP with complete remission for unknown period of time and passed away from accident without relapse of CD. (Tajima et al)

Clinical trials of corticosteroid monotherapy or IVIG in iMCD:

No clinical trials of corticosteroid monotherapy or IVIG in iMCD patients have been conducted.