Thursday, 6 November 2014

German doctors alerted 18 months ago about lymphopaenia risk on fumarates

On 25 June 2013, Biogen-Idec, and the German Federal Institute for Drugs and Medical Devices, published a safety bulletin (Red Hand Letter) warning German healthcare professionals (HCPs) about the risk of opportunistic infections in patients taking Fumaderm or initiating Fumaderm for the treatment of psoriasis. The bulletin advises that patients who develop severe, persistent lymphopaenia during Fumaderm therapy (around 3% of patients) are at risk of opportunistic infections. The letter refers to 3 cases of progressive multifocal leukoencephalopathy (PML), 1 case of Kaposi's sarcoma and 1 case of nocardiosis in such patients. Consequently, patients with white blood cell (WBC) counts below 3000 cells/mcL should discontinue use of Fumaderm. We are surprised they should set a guideline based on the total white cell count alone and not include guidance based on lymphocyte counts as well.

Fumaderm contains dimethyl-fumarate, which is also the active ingredient of Tecfidera for the treatment of MS, in addition to other fumaric acid esters. In the Phase III studies of Tecfidera in MS, WBC counts below 3000 cells/mcL were recorded in 10% (DEFINE) and 4% (CONFIRM) of patients over 2 years. It is now clear that all these issues are not specific to Fumaderm and will occur on Tecfidera.

In order to reduce the risk of such opportunistic infections, Biogen-Idec advises that HCPs strictly observe the Fumaderm product information (section 4.4), which recommends regular monitoring of blood cell counts before and during Fumaderm treatment, including every 14 days for the first 3 months of therapy. Implementing these latter guidelines for MS seem premature, but of the EMA mandate this will make using Tecfidera in clinical practice more burdensome. 

Click here for the original safety bulletin (in German) and embedded below.

Another issue that has been seen with Fumaderm that has now emerged with Tecfidera is acute renal failure (there are now two reports in the German BfArM database). This is not unexpected as acute renal toxicity is well described in the psoriasis literature (see abstracts below). It is clear that extra vigilance is now required to monitor for both haematological and renal side effects on Tecfidera. 

Abstracts of articles on renal toxicity with Fumaderm

Roodnat et al. Acute kidney insufficiency in the treatment of psoriasis using fumaric esters. Schweiz Med Wochenschr. 1989 Jun 10;119(23):826-30.
We describe two patients who developed acute renal failure during therapy with fumaric acid-esters. Histologic findings after renal biopsy in one patient were compatible with the diagnosis of acute tubular necrosis (ATN), and renal function was restored after cessation of the medication. The histologic diagnosis in the other patient was tubulo-interstitial nephritis (TIN), possibly reactive to ATN. The recovery of renal function was incomplete after 9 months. Two other patients had deterioration of renal function and proteinuria during therapy with fumaric acid-esters. The symptoms were completely reversible in one patient after discontinuation of the medication, and incompletely reversible in the other. The literature is reviewed and a comparison is drawn with the maleic acid model in the rat.

Roodnat et al. Acute kidney insufficiency in patients treated with fumaric acid esters for psoriasis. Ned Tijdschr Geneeskd. 1989 Dec 30;133(52):2623-6.
We describe four female patients with psoriasis treated with fumaric acid esters. In two patients acute renal failure developed during this therapy. Histological investigation of renal biopsy in one patient was compatible with the diagnosis of acute tubular necrosis; her renal function was reversible after cessation of the medication. The histological diagnosis of the other patient was tubulo-interstitial nephritis, possibly as a reaction to acute tubular necrosis. The recovery of her renal function was incomplete after 9 months.

Raschka & Koch. Longterm treatment of psoriasis using fumaric acid preparations can be associated with severe proximal tubular damage. Hum Exp Toxicol. 1999 Dec;18(12):738-9.
Fumaric acid preparations are used as longterm and effective treatment of psoriasis. Apart from gastrointestinal, dermatological and hematological side-effects, transient renal damage was observed during treatment with fumaric acid. The case of a 38 year old woman who was treated with fumaric acid (420 mg bid) for 5 years before she complained of fatigue and weakness. According to clinical laboratory she had developed severe proximal tubular damage. Hypophosphatemia, glycosuria and proteinuria persisted although medication was stopped immediately.

Dalhoff  et al. Acute kidney failure during psoriasis therapy with fumaric acid derivatives. Dtsch Med Wochenschr. 1990 Jun 29;115(26):1014-7.
24 days after starting treatment of psoriasis with fumaric acid derivatives (0.8-1.0 g orally, plus unknown quantities locally) a 21-year-old woman developed acute oliguric renal failure with a rise of serum creatinine levels to 1094 mumol/l (12.4 mg/dl). Deterioration of renal function had been preceded by severe abdominal symptoms with nausea, vomiting and colicky pain. On admission to hospital she was dehydrated with hyponatraemia and hypokalaemia. There was glomerular microhaematuria, increased excretion of renal epithelia, and tubular proteinuria. Renal biopsy demonstrated acute tubular damage with vacuolization of proximal epithelia, dilated tubules and scattered necroses. After intermittent haemodialysis (13 courses over two weeks) renal function gradually recovered, as demonstrated at a follow-up examination four months after discharge.

Stühlinger et al. The nephrotoxic effect of therapy with fumaric acid esters in psoriasis. Dtsch Med Wochenschr. 1990 Nov 9;115(45):1712-5.

Two sisters, aged 25 and 29 years, with generalized psoriasis guttata since childhood, developed nausea, upper-abdominal pain, loss of appetite, palpitations and flushes in the course of local and oral administration of fumaric acid esters. Because of these side effects the treatment was discontinued after about two weeks, and the symptoms disappeared. But proteinuria and haematuria were subsequently noted, creatinine concentration rose to 2.2 and 2.5 mg/dl, respectively, while creatinine clearance fell to 44 and 27 ml/min, respectively. Examination of urinary sediments and analysis of urinary proteins gave results compatible with tubular-interstitial renal damage. The abnormal renal functions and urinary findings proved reversible within three weeks.

Häring et al. Early detection of renal damage caused by fumaric acid ester therapy by determination of urinary β2-microglobulin. Br J Dermatol. 2011 Mar;164(3):648-51.
BACKGROUND: Fumaric acid esters are considered efficacious and safe drugs for the treatment of psoriasis. Renal damage, caused either by acute renal injury or Fanconi syndrome, is a recognized side-effect of this therapy. OBJECTIVES: To investigate whether the measurement of urinary excretion of β2-microglobulin, a marker of renal proximal tubular dysfunction, allows early detection of kidney damage before an increase in serum creatinine or significant proteinuria occurs.
METHODS: Urinary β2-microglobulin excretion was measured regularly in 23 patients undergoing fumaric acid ester therapy. RESULTS: Urinary β2-microglobulin remained normal in all 10 male patients. Three (23%) out of 13 female patients experienced an increase in urinary β2-microglobulin excretion. In two of these patients a sharp increase was observed in association with high doses. One further patient had moderately elevated levels on rather low doses of fumaric acid esters. After discontinuing treatment, urinary β2-microglobulin levels returned to normal within a few weeks. CONCLUSION: Determination of urinary β2-microglobulin possibly allows early detection of renal damage by fumaric acid esters. Female patients seem to be prone to this side-effect, especially when taking high doses.


  1. I'm due to start Tecfidera next month and I do feel there are concerns now about this tablet. I have a brain only MRI scan due next week after a recent possible relapse.

    1. Monitoring is key! These 'news' aren't really new as the effects of fumarates were known over many years. No manufacturer likes to dwell on adverse effects of their drugs, however taken as what they are - manageable adverse effects provided monitoring is in place - one shouldn't poor the baby with the bathwater. There simply is no 'fire-and-forget' pill for MS!

  2. I have been on Tecfidera for 2 months
    After one month my bloods were taken
    WBC 2.8
    Neutrophils 1.20
    Lymphocytes 1.17
    Should I be concerned ? They request further blood tests 3 months then 6 months.
    They take FBC differential, LFT, U/E,

    1. Difficult to give individual advice over the blog. You need to discuss this with your doctor/MS nurse. According to the German letter your WBC's would be below their threshold (3,0), however lymphocytes are essentially normal, thus I'd say no concern atm, but I have to reiterate - please talk to the team looking after you!

  3. What is the concern from low wbc ? Will it drop further while on tecfidera ? Thank you for your response. My neurology team know the blood results and are not alarmed.

    1. WBC is not the best index of white cell toxicity here as it includes *all* white cells; lymphocytes are more meaningful. You seem to be in good hands!

  4. Thank you for your responses, I hope you are very well.
    Perhaps the Neuro team are not fully updated about these issues. I have many concerns in relation to treatments.
    With Tecfidera does the Stratify JC Count ? I am Positive with Titer count 3.57 . Should this connect in the same way for Tecfidera as it was with Tysabri ?

  5. Censorship does not help out ...

    I find it very strange that Prof G went in and censoring a previous commentary posts regarding the Active substance in Tecfidera is Dimethyl fumarate (or fumaric acid).

    This Active substance, fumaric acid, has in psoriasis caused severeal cases of PML. And yet, the treatment within psoriasis has a duration of 3 months treatment cycles as oppposed to RRMS, that could go on for years.

    It is clearly understood, that the Active substance of Tecfidera, Fumaric Acid, has some risk with regard to opportunistic infections, and ultimately in severe cases cases, risk for PML and septic chock.

    I was myself taken off Tecfidera, becuase I had a septic chock. Let us not hide this risks.

    So my Point is, if Prof G have have a different opnion, than what this previous signature had in a posted comment withg regard to risks with Tecfidera, it would be better.

    Censporship on vital questions, this time in relation to tecfidera, or any other agent for that matter, is not in the interest of patients well being

    If Prof G or his Associates have a different opinion on a matter, they can make their case with good argument. But to censor a well written comment (don´t remember the signature) are not in the patients interest.

    Silva Rothstein, Germany

    1. I had to remove a comment that stated the patient who died from PML was from Germany. We have no way at present of verifying this information. In addition, someone implied that neurologist looking after the patient was at fault. Again until we have more information we cannot allow these types of claims. If you have read my posts on this issue it is clear I think Tecfidera and Fumaderm have the same safety issues and this is driven via leukopaenia, and in particular lymphopaenia, and we need to wait to see what emerges in relation to DMF's mode of action.

      At present I don't think anything changes in relation to Tecfidera's risk:benefit profile provided you don't let yourself stay on the drug with a low lymphocyte count. At present the latter is set as a cut-off of 0.8 or 800, but could potentially be lowered to 0.5 or 500 if it is shown that the lymphopaenia is reversible.

      So yes, if you become lymphopaenic on Tecfidera and remain so for an extended period of time it is immunosuppressive and you are at risk of opportunistic infections. This is no different to other immunosupressive drugs, for example azathioprine. I have however, differentiated fingolimod, and other emerging sphingosphine-1-phosphate modulators, from this based on their mode of action.

    2. If you make false claims there may be legal consequences and so until the information claimed can be verified, it is prudent toremove it. It is not is common sense

  6. Perhaps the Neuro team are not fully updated about these issues.
    I have many concerns in relation to treatments.
    With Tecfidera does the Stratify JC Count ? I am Positive with Titer count 3.57 .
    Should this connect in the same way for Tecfidera as it was with Tysabri in relation to PML?

    1. Re: "With Tecfidera does the Stratify JC Count ?"

      Only if you have a prolonged lymphopaenia on DMF or tecfidera. The risk of PML is not the same with Tecfidera and Natalizumab; it appears only to be there if you low lymphocyte counts.


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