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. 2014 Feb 4;175(3):425–438. doi: 10.1111/cei.12226

Table 1.

Infectious aspects of immunomodulating and immunosuppressive therapies for multiple sclerosis (MS).

Active substance† Trade name Warning notices‡ Adverse events and side effects‡
Methylprednisolone e.g. Urbason
  • Critical use under the following conditions; add calculated anti-infective treatment where appropriate:
    • Acute viral infection (e.g. herpes zoster, herpes simplex, varicella, keratitis herpetica)
    • Hbs-antigen-positive chronic active hepatitis
    • Up to 8weeks before and 2 weeks after live vaccines
    • Systemic mycosis and parasitosis (e.g. nematodes)
    • Poliomyelitis
    • Lymphadenitis following BCG-vaccination
    • Acute and chronic bacterial infections
    • History of tuberculosis (cave: reactivation), treat latent TB infection

  • Steroid-associated immunosuppression increases risk of opportunistic infections

  • Aggravated courses of viral diseases (chickenpox, measles) possible

  • Immunosuppressed children and adults without history of chickenpox or measles are at increased risk: consider post-exposition prophylaxis

  • Increased risk of viral infections of potentially severe or fatal course of disease (varicella, herpes simplex and during viraemic phase of herpes zoster)

  • Masking of infections

  • Exacerbation of latent infections
Interferon beta-1a Avonex

  • Anti-viral effects of type I interferons per se documented

  • No special warning notices in the context of infection

 Abscess formation at injection-site, incidence unclear
Rebif

  • No special warning notices in the context of infection

  • Anti-viral effects of type I interferons per se documented

  • In case of injection-site lesions follow-up by physician

 Occasional abscess formation at injection site (incidence in relevant trials between >1/1000 to <1/100)
Post-marketing reports (incidence unknown): systemic infections including parasitosis and infections at injection site
Interferon beta-1b Betaferon, Betaseron

  • Contains human albumin causing potential risk of transmission of viral diseases

  • Theoretical risk of transmission of Creutzfeld–Jacob disease (CJD) cannot be ruled out

  • Anti-viral effects of type I interferons per se documented

  • In case of injection-site lesions follow-up by physician

  • In case of neutropenia high frequent/low threshold search for infection

 Analysis of 1093 patients (placebo 965) from four pooled trials:

  • Manifestation of any infection: 6–14% (3–13%)

  • Abscess formation: 0–4% (1–6%), no statistically significant differences

  • Sinusitis: 4–36% (6–26%), no statistically significant differences
Extavia

  • Contains human albumin causing potential risk of transmission of viral diseases

  • Theoretical risk of transmission of CJD cannot be ruled out

  • Anti-viral effects of type I interferons per se documented

  • In case of injection-site lesions follow-up by physician

  • In case of neutropenia high frequent/low threshold search for infection

 Analysis of 652 patients (placebo 534) from two pooled trials

  • Upper airway infections: 3–18% (2–19%), no statistically significant differences [130–132]
See Betaferon/Betaseron
Glatiramer acetate Copaxone

  • No special warning notices in the context of infection

 Analysis of 269 patients (placebo 271) for 35 months [42,133]
Frequent (>1:100, <1:10):

  • Bronchitis, cough, rhinitis

  • Herpes simplex (>2% more frequent compared to placebo)

  • Vaginal candida mycosis (>2% more frequent compared to placebo)

  • Cystitis
Occasional (>1:1000, <1:100):

  • Pyelonephritis
Fingolimod (FTY 720) Gilenya Contraindications

  • Immunodeficiency syndrome

  • Opportunistic infections

  • Treatment-associated Immunosuppression

  • Active infections (acute and chronic hepatitis or tuberculosis)

 Side effects [48,49]:
Caveats

  • Normal blood cell count, not older than 6 months before treatment initiation

  • Pause treatment if lymphocyte count <0·2 × 109/l

  • No treatment initiation with ongoing acute infection

  • Test for VZV antibodies if patients have no history of chicken-pox or VZV vaccination

  • in case of missing VZV-antibodies consider vaccination and postpone treatment initiation for 30 days

  • FTY-treatment can increase risk of infections

  • In case of infection-associated symptoms perform appropriate testing and consider treatment

  • Consider FTY treatment interruption in case of severe infection and re-evaluate indication

  • Enforced surveillance respective infections up to 2 months after FTY treatment

  • Keep patients informed with respect to increased risks of infections

 Very often (>1:10)

  • Influenza infection
Frequent (>1:1000, <1:10):

  • Herpes virus-infection

  • Bronchitis

  • Sinusitis

  • Gastroenteritis

  • Tinea infection
Occasional (>1:1000, <1:100):

  • Pneumonia
Overall similar rates of infections (69 versus 72%) and severe infections (1·6 versus 2·6%) in MS patients comparing pooled 0·5 mg and 1·25 mg FTY versus placebo [48].
Lower airway infections, especially bronchitis and pneumonia more often with FTY treatment.
Two cases of fatal herpes infection (1·25 mg FTY/day)

  • Delayed start of acyclovir treatment in a case of HSV encephalitis

  • Primary disseminated VZV infection in context of former missing exposition to VZV and concurrent high-dose steroid course for MS relapse treatment
Third case of disseminated VZV-infection 39 months after initiation of FTY-treatment during follow up of TRANSFORMS [134]
Teriflunomide Aubagio Contraindications:

  • Immunodeficiency

  • Disturbances of bone marrow function

  • Severe and uncontrolled infections

  • Patients may be more likely to get infections including opportunistic infections

  • Single case of fatal sepsis following pneumonia due to Klebsiella spp. infection.

  • Fatal cases of Pneumocystis jiroveci pneumonia and aspergillosis with underlying rheumatoid arthritis and concomitant immunosuppressive treatment

  • Reactivation of CMV (cytomegalovirus)-associated hepatitis

  • Delay treatment initiation in case of active acute or chronic infections

  • In case of severe infection consider discontinuation of treatment and /or procedure for accelerated elimination

  • Keep patients informed about likelihood for infections and necessity regular follow-up

  • Screen for tuberculosis (TB) before treatment initiation, use standard TB treatment regimen where required
Natalizumab Tysabri

  • Exclude immunosuppression before treatment

  • Increased risk for opportunistic infections

  • Risk of progressive multi-focal leucencephalopathy (PML), worldwide 372 cases from 115·365 natalizumab-exposed patients, 83 deaths (23%) (as of 4 June 2013 [135])

 Analysis of placebo-controlled trials with 1617 patients (placebo 1135) and 2-year treatment duration
Often (>1:1000, <1:10):

  • Urinary tract infection

  • Nasopharyngitis
Single case of uncomplicated cryptosporidium-associated diarrhoea
Single case of fatal herpes encephalitis
PML (two cases in MS trials, single case in Crohn's disease trial)
Mitoxantrone e.g. Ralenova
  • Contraindications:
    • Severe acute infections
    • Neutrophil granulocyte count <1500 cells/mm3 (exception: treatment of acute non-lymphocytic leukaemia)

  • Before treatment initiation exclude or treat infection

  • Treatment steering and dose adjustment following blood cell count post last or pre new treatment cycle having regard to recent history of infection

  • In-vitro analysis showed no per se anti-microbiotic effect of mitoxantrone in concentrations less than 10 mg/l

 Side effects:
Very often (>10%)

  • Urinary tract infections

  • Upper airway infection
Unknown incidence:

  • Overall infections

  • Pneumonia

  • Sepsis

  • Opportunistic infections
Off-label setting:
Rituximab MabThera Contraindications:

  • Active and/or severe infections (e.g. tuberculosis, sepsis, opportunistic infections)

  • Severe immunodeficiency (e.g. hypogammaglobulinaemia, reduced CD4-or CD-8 cell count)

  • Extraordinary attention if neutrophil granulocyte count <1·5 × 109/l.

  • Precaution in case of history of recurrent or chronic infections or other concomitant diseases, increasing the risk of infection

  • Clinical surveillance regarding infections between treatment cycles

  • Sufficient testing and treatment of infection following application if required

  • Reactivation of hepatitis B including fulminant courses

  • Very rare manifestation of progressive multifocal leucoencephalopathy (PML) in patients with non-Hodgkin lymphoma (NHL), post-launch

  • PML cases after off-label use in systemic lupus erythematosus and vasculitis and precedent or concomitant immunosuppressive treatment according to surveillance reporting system.

  • No PML-reports with patients suffering from rheumatoid arthritis (RA)

  • PML manifestation in patients with autoimmune-disease without rituximab exposition
Rheumatological indication:

  • Overall infection rate 0·9 per patient-year

  • Predominance of upper airway and urinary tract infections

  • Rate of relevant, partly fatal infections 0·05 per patient-year

Phases II and III trails in RA (R-MTX versus MTX; n: 540 versus 398) [136–138]:

  • Any infection: 37–41% versus 30–37%

  • Urinary tract infections: 5–6 versus 4–8%

  • Upper airway infections: 13–16 versus 12–15%

  • Lower airway infections/pneumonia: 3–4% versus 2–5%

Haematological indication:
Side effects according to clinical trials (n: 356 NHL patients, monotherapy):

  • Deprivation of B cells in 70–80% of patients

  • Decrease of immunoglobulins only in rare cases

  • Overall 30·3% infections, independent of causal connection

  • 3·9% severe (grade 3 and 4) infections including sepsis (1·4% during and 2·5% after treatment)

Post-marketing-surveillance:

  • Very rare (<1:10·000): severe virus infections: manifestation, reactivation and deterioration of herpes virus group-associated (CMV, VZV HSV) diseases, JC-virus and hepatitis C virus

Azathioprine e.g. Imuran Contraindications:

  • Treatment initiation with pre-existing severe infection under strict risk–benefit consideration only

  • Immunization with live vaccines

  • Immunosuppression can cause severe VZV infections (chickenpox, herpes zoster)

  • Check history of VZV infection, consider testing for previous exposition

  • Consider passive VZV immunization in VZV antibody-negative patients with contact to patients with chickenpox or herpes zoster

 Occasional (>1:1·000, <1:100)

  • Viral and bacterial infections as well as mycosis

  • Increased risk of infection including severe and atypical manifestations of VZV or other infectious diseases, especially under combination therapy with glucocorticosteroids
Cyclophosphamide e.g. Cytoxan Contraindications:

  • Active infections

  • Cystitis

  • Rehabilitate from infection before treatment initiation

  • Accurate oral hygiene

  • Blood cell count and urinary sedimentation test on a regular basis

  • Strict monitoring of patients with pre-existing hepatitis because reactivation of hepatitis after cyclophosphamide treatment reported

  • Mesna-prophylaxis (reduction of urinary tract toxicity and secondary infections)

  • Interstitial pneumonia and other infections in the context of conditioning treatment in haematology

  • Secondary colonization following initially sterile haemorrhagic cystitis
IVIg e.g. Octagam

  • Transmission of possibly unknown infectious agents cannot be ruled out when using drugs deriving from biological material/human donors

  • Existing inactivation and elimination procedures might be of restricted value for non-or uncoated viruses

 Infection risk: see warning notices
†

Not all substances listed here are licensed for the treatment of MS; some are given on an ‘off-label use’ basis.

‡

Warning notices and side effects following the current European and American prescribing information as available from the manufacturer (Status 06/2013). Hbs antigen: hepatitis B surface antigen; BCG: Bacillus Calmette–Guérin; VZV: varicella zoster virus; RA: rheumatoid arthritis; MTX: methotrexate; HSV: herpes simplex virus; JC virus: John Cunningham virus; IVIg: intravenous immunoglobulin.