New articles posted here - update 6-28-17

Yes, that is the effect, that even though it is second line it is treated as being ahead of all the others in that group.

I just reread the 11-5 article on CD8+ T cell........ and noticed the mention of Vitamin D as a mediator of T cells and potentially being helpful with autoimmune diseases. Are there any patients here who have mentioned Vitamin D as helping with their counts? How about with SLE (Ellen might be headed in that direction)?

I don't have citations available, but there has been some buzz that vitamin D could be problematic for some immune disorders like SLE.
Erica

Rob16 wrote: I just reread the 11-5 article on CD8+ T cell........ and noticed the mention of Vitamin D as a mediator of T cells and potentially being helpful with autoimmune diseases. Are there any patients here who have mentioned Vitamin D as helping with their counts? How about with SLE (Ellen might be headed in that direction)?

I don't know if vitamin D has helped with my counts but my haematologist has started checking everyone's vitamin D levels regularly. Mine was low and I got it back to normal range with supplements but I couldn't say if it helped stabilise my counts.. who knows?

The doctor I had in emergency today quoted what he believed were the first line treatments. IVIG Pred and splenectomy.

This is a new article from April 2013 on the use of High Dose Vitamin D along with Plaquenil to combat ITP. I am particularly interested in the Vitamin D aspect, as it ties in with the article posted above on 11-5.

www.jmedicalcasereports.com/content/7/1/91

Case report
Refractory immune thrombocytopenia successfully treated with high-dose vitamin D supplementation and hydroxychloroquine: two case reports

Abstract
Introduction

Immune thrombocytopenic purpura is thought to be characterized by an immune response against the host’s own platelets. If the thrombocytopenia is severe, patients are initially treated with high-dose steroids. Other more toxic second line treatments are considered if steroids fail. Here, we report the case of two patients in whom conventional treatment was unsuccessful but who responded to hydroxychloroquine and high-dose vitamin D replacement therapy. To the best of our knowledge, this is the first description of successful treatment for immune thrombocytopenia with high-dose vitamin D and hydroxychloroquine.
....
Conclusions

In our two case reports, we found an association between vitamin D deficiency and immune thrombocytopenia where platelet levels responded to vitamin D treatment and hydroxychloroquine but not to prednisone. We believe there may be synergism between vitamin D supplementation and hydroxychloroquine. The mechanism by which high-dose vitamin D results in increased platelet counts in immune thrombocytopenia patients is unknown. However, vitamin D has long been thought to play an immunomodulatory role, which may include a dampened immune response in patients with immune thrombocytopenia or other autoimmune diseases.

ekein wrote:

I don't have citations available, but there has been some buzz that vitamin D could be problematic for some immune disorders like SLE.
Erica

Erica, do you think you may have read about problems with SLE and sunlight (which I have read about) and remembered it incorrectly as Vitamin D? If you were correct, I would appreciate any citations you can find, as Ellen is about to become a Vitamin D guinea pig!

No, Erica is referring to this:

www.news-medical.net/news/2009/04/09/48189.aspx

Excuse me for saying so, but Erica wouldn't confuse sunlight and Vitamin D! Too much intelligence in that head of hers!

Very interesting find on the Plaquenil/Vitamin D article. When my 9 year ITP remission began, I had just started Plaquenil. I've never been able to pin point what caused the remission since I also started on Prednisone at that time and have not been off of it since.

I have a long history with low Vitamin D and have taken high dose prescription D for a few years. The OTC supplements didn't do anything for me and it took 14 months of 50,000 IU's a week to get me to a normal level. Have Ellen's levels been tested? You should do that before starting it so you have a baseline.

Pre-publication article on clinical trial of Plaquenil for ITP: (American Journal of Hematology)

onlinelibrary.wiley.com/doi/10.1002/ajh.23609/abstract
Hydroxychloroquine is a good second-line treatment for adults with immune thrombocytopenia and positive antinuclear antibodies.
Abstract:
Treatment of patients with lupus-associated thrombocytopenia (SLE-ITP) is not standardized. We report data on efficacy and safety of hydroxychloroquine (HCQ) in this setting and in ITP patients with positive antinuclear antibodies (ANA) without definite SLE. Inclusion criteria were: definite diagnosis of ITP with a platelet count (PLT) <50 × 109/L, ANA ≥ 1/160 on Hep2 cells with or without a definite diagnosis of SLE, and no sustained response to at least one previous treatment-line and treatment with HCQ. Response criteria were Complete Response (CR) for PLT ≥ 100 × 109/L and Response (R) for PLT ≥30 × 109/L and at least twice the initial value. Forty patients (32 females) with a mean age of 35 ± 17 years and PLT at ITP diagnosis of 14 ± 13 × 109/L were analyzed. Twelve (30%) patients had a SLE-ITP, 28 patients had only positive ANA. All the patients failed to respond to oral prednisone with a median of two treatment-lines (1–5) before HCQ which was initially given in combination with another ITP treatment in 36 patients. Overall response rate was 60% (24/40) including 18 lasting CR and six lasting R maintained with a median follow-up of 64 months (6–146), in ¾ of cases with only HCQ and no concomitant ITP treatment. The response rate (CR+R) was higher in the SLE group vs ANA-positive group (83% vs 50%, P < 0.05). No patient stopped HCQ because of a side-effect. HCQ appears to be a safe and effective second line treatment for patients with SLE-ITP or ITP and high titer of ANA. This trial was registered at www.clinicaltrials.gov as # NCT01549184. Am. J. Hematol., 2013. © 2013 Wiley Periodicals, Inc

It doesn't surprise me that Plaquenil would help Lupus/ITP since Plaquenil is known to suppress antibodies. I've always suspected that it could cause remission for some people. Since ITP can be a symptom of Lupus, getting Lupus under control could definitely make a difference with ITP.

Ellen's Vitamin D levels will be tested next CBC along with repeat ANAs (she has one positive and one negative). It looks like she has enough symptoms to diagnose SLE already, but hasn't seen a rheumatologist.

Good advice on getting a Vitamin D baseline before starting supplements.

Sandi wrote:

No, Erica is referring to this:
www.news-medical.net/news/2009/04/09/48189.aspx
Excuse me for saying so, but Erica wouldn't confuse sunlight and Vitamin D! Too much intelligence in that head of hers!

You are so right about Erica!
That article you cited looks kinda iffy, though. I followed the link back to autoimmunityresearch.org/
and found an organization far outside the mainstream. Not much into peer review!
Sometimes the kooks are proven right, though!

Yes, I agree about the article. I tried to find more and a bunch of them popped up, but they all cited the exact same source and were all around the same date. Considering what can happen if D is low, I chose to treat it.

Thanks for looking deeper into the D/auto immune disease article. I hadn't, obviously. I think there is something going on with D and auto immune disorders and I think we might have some interesting breakthroughs in this area. So many on this forum have brought up low D levels.

I've not had mine checked but I'm a good candidate to have low levels, I avoid sun far more than most - I have a new project in Honolulu (yes!) and I walk around with a big hat, long sleeves and even long gloves. I get hives from just a few minutes of exposure. Lucky for me Hawaii is lovely in the evening and at night. And I have an indoor job.

If I can remember I'm going to ask my dr. to check my D levels. Interested to see what you report Rob.
Erica

Erica - I'd bet that you do have low D. Let me know how that turns out. My daughter with Graves even has low D and she is in the sun a lot. Seems to be very common with autoimmune disorders, especially those with Lupus.

Background: Adults with newly-diagnosed and persistent ITP usually respond to steroid based treatments such as prednisone but relapse with tapering. One 4-day cycle of Dexamethasone (dex) at 40 mg/day in newly diagnosed ITP resulted in a lasting effect in 50% of patients (pts) in 1 study. An Italian study showed that 3 cycles of dex are better than 1 cycle. Approximately 50% of pts with chronic ITP experience a complete or partial response (CR & PR) to rituximab, yet only 20% of pts have a lasting, unmaintained response after 3 years. Mechanistically, rituximab (which depletes B cells but not plasma cells) and dexamethasone (which may be the most potent anti-plasma cell agent) are a logical combination in treatment of antibody-mediated diseases such as ITP. In 2 studies of newly-diagnosed pts, dex 40mg/day x 4 followed by rituximab was more effective than dex alone (one study added more dex half way through). In our pilot study, pts at Weill Cornell Medical College (WCMC) with all stages of ITP were treated with a combination of rituximab (R) and usually 3 cycles of dex. The outcome of this combination was retrospectively analyzed.

Methods: Combination of standard-dose rituximab (weekly x 4) and usually 3 4-day cycles of 28mg/m2 (max. 40mg) dex at 2-week intervals (R+3Dex) was explored in 67 pediatric and adult pts with ITP at WCMC. Patients were monitored with CBCs obtained weekly and then at less frequent intervals if a response was achieved. Best response (after 8 weeks to avoid transient effects of dex) was determined. Patients were categorized as CR (platelet count≥100x109/L) or PR (50-100x109/L). Relapse was defined as either two consecutive platelet counts <50x109/L and/or need for additional therapy. The duration of response was calculated from date of first rituximab administration to relapse or latest follow-up as of July 31st 2013.

Results: Overall, 50 of 67 pts treated with R+3Dex achieved a best response of either a CR (n=43) or a PR (n=7) at 8 weeks or later from start of therapy for an overall response rate of 75%. Seventy-three percent of pts received R+3Dex; variations were primarily in the timing and amount of dex given. Fifteen responders, 9 CRs and 6 PRs, relapsed at a median of 9 months. Seventy percent of the responders (or 52% of all pts treated) maintain a continuous response with platelet counts ≥ 50 x 109/L as of their last visit at a median f/u of 20 months. Kaplan Meier Analysis estimates 44% of all pts treated (Figure) and 59% of responders (Figure) maintained a best response without relapse at 67 months after initiating treatment. If only those with ITP ≤ 24 months are included, the estimated long term response rate is 59% (p=0.0017) versus only 19% for those with a duration of ITP > 24 months (Figure). Of 36 responding children and adults who had ITP ≤ 24 months, 29 continued to respond as of last follow up. Adults initially responded better than children (p=0.0019) but the long-term responses were not different (Figure). Pts achieving a CR had longer response than those achieving a PR.

Adverse events related to R+Dex were usually mild-moderate, although 3 pts had serum sickness and 2 had transient colitis. IgG levels fell to below the lower limit of normal for age in 14 of 67 pts, 10 of whom had their IgG levels return to normal. In 6 of 14, IgG levels were < 400 mg/dl, some of whom received IVIG. Fifteen patients had serial BK/JC levels without ever detecting virus.

Conclusions: R+3Dex provides clearly superior results to rituximab alone. Notably, there was a 75% response rate overall (50/67 pts) compared to 50% with R alone. The 5 year response rate was almost 50% of all patients and 3/5 of responders. In patients who had had ITP for ≤ 2 years, the response is comparable to what has been reported with splenectomy. Specifically the results in the ≤ 2 year group suggest that R+3Dex is an effective way to induce indefinitely normal platelet counts in pts with a “short” duration of ITP. R+3Dex was tolerable although patients had difficulty with 3 cycles of dex. The 21% rate of hypogammaglobulinemia, higher than that seen with R alone, is also evidence of the mechanism of R+3Dex affecting both B cells and plasma cells. The lasting, long-lived, unmaintained responses observed in this study suggest that this combination therapeutic strategy should be further tested in a controlled trial in patients with newly diagnosed, persistent, and early chronic ITP, whether or not they have been previously treated with other agents.

ash.confex.com/ash/2013/webprogram/Paper62543.html

ash.confex.com/ash/2013/webprogram/Paper57670.html

Yes the results in that article are interesting. My haematologist told me just last week that he had a number of patients who had used Nplate and been able to stop using it keeping a good count. He said it happened more often than with other treatments and was unexpected.

I did comment that I found it a bit worrying that it was something totally unexpected and wonder what other unexpected effects might appear later on!

True enough! Maybe nothing else will happen and it will all be good!

I always wonder why it jump starts remission. A valid reason would be nice at some point.

asheducationbook.hematologylibrary.org/content/2013/1/276.long

Something new from the University of Louisville:

A combination of bortezomib and rituximab yields a dramatic response in a woman with highly
refractory immune thrombocytopenic purpura: a case report
Abstract
Introduction
Chronic refractory immune thrombocytopenic purpura can be a challenging condition to treat. By definition, the standard first and second line treatments have failed in these patients and modalities such as thrombopoiesis-stimulating agents and more intensive immunosuppressive drugs are therefore used. However, there still remains a subset of patients who continue to be refractory to treatment.
Case presentation
We present the case of a 30-year-old Hispanic woman with recurrent intracranial bleeds, in whom multiple lines of treatment had failed. She was treated with a combination of bortezomib and rituximab based on previously published data that suggested this therapy effectively blocks all antibody-producing cells. Our patient’s platelet counts rapidly improved and subsequently normalized following this treatment.
Conclusion
To the best of our knowledge, this case represents the first report of the effective use of
bortezomib and rituximab in highly refractory immune thrombocytopenic purpura. We believe further study of this therapy is warranted in this setting.
www.jmedicalcasereports.com/content/pdf/1752-1947-8-19.pdf

Bortezomib is a proteasome inhibitor used for treating relapsed multiple myeloma and mantle cell lymphoma. It is marketed as Velcade by Millennium Pharmaceuticals and Cytomib by Venus Remedies.

Association of autoantibody specificity and response to intravenous immunoglobulin G therapy in immune thrombocytopenia: a multicentre cohort study.

Peng J, Ma SH, Liu J, Hou Y, Liu XM, Niu T, Xu RR, Guo CS, Wang XM, Cheng YF, Ni H, Hou M.
Author information
Abstract
BACKGROUND:

Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder, in which platelet GPIIb/IIIa and GPIb/IX are the two most frequently targeted autoantigens. Our previous studies in animal models of ITP demonstrated that intravenous immunoglubin G (IVIG) could protect against anti-GPIIb/IIIa-mediated thrombocytopenia but failed to ameliorate ITP induced by most anti-GPIb/IX antibodies.
OBJECTIVES:

The objective of this human study was to evaluate the association between the specificity of anti-platelet autoantibodies and response to IVIG treatment.
PATIENTS/METHODS:

In this retrospective study, a cohort of 156 previously untreated adults with severe ITP who underwent IVIG therapy (0.4g/kg/day for 5 days) was analyzed. The primary outcome was response defined as platelet counts ≥ 30 × 109 /L and doubling of baseline counts within 7 days of dosing, and absence of bleeding.
RESULTS AND CONCLUSIONS:

Among the 66 patients with anti-GPIb/IX antibodies, only 24 (36.4%) achieved a response, as compared with 72 of 90 patients (80.0%) who were negative for anti-GPIb/IX antibodies (relative risk 2.2, 95% confidence interval 1.6-3.1). This study found no difference in response between patients with autoantibodies to GPIIb/IIIa (61.7%) and those without anti-GPIIb/IIIa antibodies (61.3%). Logistic regressions, including main effects and the interaction between these two antibodies, showed no influence of anti-GPIIb/IIIa antibodies on the effects of anti-GPIb/IX antibodies with regards to their association with IVIG response. Thus, in adults with ITP, the presence of anti-GPIb/IX autoantibodies is a predictive factor for poor response to IVIG treatment. Trial registration: ClinicalTrials.gov NCT01666795. This article is protected by copyright. All rights reserved.


www.ncbi.nlm.nih.gov/pubmed/24517219

Sustained response after discontinuation of short-and medium-term treatment with eltrombopag in patients with immune thrombocytopenia.

Abstract

Eltrombopag is effective and safe in chronic immune thrombocytopenia (ITP) patients not responding to previous therapy. However, when eltrombopag is discontinued, platelet counts usually return to baseline within 2 weeks. Here, we describe the clinical characteristics of the, to the best of our knowledge, largest case series of patients with ITP, who presented sustained responses after discontinuing eltrombopag (n = 12). The median time from diagnosis to eltrombopag initiation was 24 months (range, 1-480). The median number of prior therapies was 5 (range, 1-7), and the median duration of eltrombopag treatment was 5 months (range, 1-13). Three patients received eltrombopag for only 1 month. The treatment was well-tolerated. The median (range) follow-up of this case series was of 7 months (6-20), during which all patients maintained a safe platelet count without the need for anti-ITP treatment. The communication of such cases may support the conduction of new studies to investigate which predictive factors could identify ITP patients with sustained responses after discontinuing eltrombopag without additional therapy. The need of long-term use of eltrombopag should be re-examined.

www.ncbi.nlm.nih.gov/pubmed/24499036

Abstract The activation status of platelets in Immune Thrombocytopenia (ITP) patients - which is still somewhat controversial - is of potential interest, because activated platelets tend to aggregate (leading to excessive clotting or thromboembolic events) but cannot do so when platelet numbers are low, as in ITP. Although corticosteroids are the first line of therapy in ITP, the effect of steroids on activation of platelets has not been evaluated so far. We examined the status of platelet activation (with and without stimulation with ADP) in ITP patients, at the start of therapy (pre-steroid treatment, naive) and post-steroid treatment (classified on the basis of steroid responsiveness). We used flow cytometry to evaluate the levels of expression of P-selectin, and PAC-1 binding to platelets of 55 ITP patients and a similar number of healthy controls, treated with and without ADP. We found that platelets in ITP patients exist in an activated state. In patients who are responsive to steroids, the treatment reverses this situation. Also, the fold activation of platelets upon treatment with ADP is more in healthy controls than in ITP patients; treatment with steroids causes platelets in steroid-responsive patients to become more responsive to ADP-activation, similar to healthy controls. Thus steroids may cause changes in the ability of platelets to get activated with an agonist like ADP. Our results provide new insights into how, and why, steroid therapy helps in the treatment of ITP.



www.ncbi.nlm.nih.gov/pubmed/24617442

We found that platelets in ITP patients exist in an activated state. In patients who are responsive to steroids, the treatment reverses this situation.

Steroids are also used in the treatment of recurring migraines. I have never heard explained why they are effective, but this study may hold the answer. One theory of migraines involves the aggregation of platelets, so deactivating the platelets would lessen platelet aggregation and prevent migraines . It would be interesting to see this same study done on migraine patients.

This might also explain why ITP patients sometimes exhibit bruising even though their CBC shows adequate platelet levels; if they are taking steroids the steroids may be interfering with clotting. Also, this might explain why patients with Cushing's Disease/Syndrome are prone to bruising: excessive cortisol may be blocking the ability of their platelets to clot.

Does anyone have a clue why steroids increase platelet counts?

Fascinating article. I read it on Facebook today and was wondering if anyone had any thoughts.

Rob:

The theory is that steroids suppress antibody production which in turn causes less platelet destruction. Sort of the same reason they work for allergies....suppress the immune system and stop the overreaction to external factors.

If that is true then I would expect a much higher rate of illness due to the immunosuppression. Steroids seem to work in a much better (more specifically) targeted manner than that. I wonder if, since we now know that steroids directly influence platelets, if they might block antiplatelet antibodies from attaching to platelets. Just speculating!

As far as I know steroids inhibit the production of interleukin-1. The other immunosuppressants we might use, mychophenolate and azathioprine work differently and inhibit purine production.

I don't have time to look it up as I have to go to work but it'll all be on google somewhere.

I believe that IVIG works like that, blocking the antibodies from attaching to platelets (indirectly).

I never really researched exactly how Prednisone works, but I do know that it suppresses antibodies for many autoimmune disorders. As far as illnesses, there are other parts of the immune system that work too...spleen, lymph nodes, thymus, white cells, etc....