Buku Medicine

DMARDs

Disease-Modifying AntiRheumatic Drugs - General principles

Prescriber takes responsibility for the patient adhering to monitoring guidelines
Monitor both the absolute values and the trends
Local areas will often have their own guidelines (e.g. http://www.northoftyneapc.nhs.uk/wp-content/uploads/sites/6/2018/10/Immune-Modifying-Drugs-Monitoring-guidance-July-2018-v0.1.pdf)
Consider urgent retesting in patients on DMARDs who present with cough, dyspnoea, abnormal bruising or bleeding - most can cause bone marrow suppression
The potential list of DMARDs (and their associated features) is long, however many DMARDs are no longer in use (e.g. Gold) or used very rarely (e.g. ciclosporin). The commonest DMARDs used in inflammatory arthritis are methotrexate, sulfasalazine and leflunomide. The commonest DMARDs used in connective tissue disease are azathioprine and mycophenolate.

No blood monitoring	Apremilast, Hydroxychloroquine, Minocycline
Regular blood monitoring	Azathioprine, Methotrexate, Mycophenolate, all biologic DMARDs, Gold, Leflunomide, Sulfasalazine*

Standard DMARD blood monitoring

Tests:
- FBC, U&Es, LFTs, CRP
Frequency - this will depend on local guidelines and clinical requirements but generally:
- For non-biologic DMARDs:
  - Every 2 weeks until on stable dose for 6 weeks
  - Then monthly for 3 months until on a stable dose for 3 months
  - Then at least 3 monthly
  - Combination of methotrexate and leflunomide – extend monthly blood monitoring until at least 12 months, decision to increase based on results
- For biologic DMARDs:
  - Every three months
  - Tip - DMARDs do not generally cause anaemia - so consider alternative causes

Drug specific factors:

Methotrexate:
- Methotrexate can rarely cause an acute pneumonitis that presents with cough, fever and progressive shortness of breath. Onset is usually within the first year of treatment. It requires urgent assessment and treatment is usually with cessation of methotrexate, folinic acid 15mg QDS and corticosteroids. Liaise with rheumatology.
Leflunomide
- Leflunomide can increase blood pressure. For mild rises treat as per guidelines. For significant increases or those resistant to therapy, liaise with rheumatology.
- Leflunomide can be a cause of weight loss. If significant (>10%) and no other cause identified liaise with rheumatology.
Sulfasalazine:
- Very rarely sulfasalazine can cause a severe rash that generally presents in the first months after starting treatment. There is associated systemic upset and they require urgent assessment.

Drug interactions:

This list is not exhaustive but these are serious interactions that most commonly cause problems. Problems most commonly arise when prescribing antibiotics and warfarin - check first!

Methotrexate with trimethoprim/cotrimoxazole - risk of serious myelosuppression
Azathioprine with trimethoprim/cotrimoxazole, allopurinol or febuxostat - risk of serious myelosuppression

Monitoring

Seek advice if concerned about values outside of normal range. For mild abnormalities (neutrophils >1.8, ALT<x2 upper limit of normal) patients are usually asked to stop treatment and recheck in 1-2 weeks.

Neutropenic patients should be advised of the risk of serious infection and to seek urgent medical attention if they develop a fever, sore throat or become unwell.

Some drugs (e.g. methotrexate) are renally excreted and so progressive changes in renal function can increase toxicity.

Chronic low-level rises in ALT/AST can indicate significant liver disease. Advise patients to stay within recommended alcohol limits and aim for a healthy weight. Have a low threshold for investigating with US abdomen and discuss with the liver team. Calculating a FIB-4 score can be helpful. If fatty liver or cirrhosis is identified, flag this with the treating rheumatologist.

DMARDs and pregnancy

Detailed guidelines on the use of DMARDs in preconception and pregnancy can be found in the BSR guidelines (below).

Patients with rheumatic diseases on any form of immunosuppression should discuss their pregnancy plans with their hospital team. Treatment regimes may be altered in advance of conception to ensure the patient is on appropriate and adequate treatments to safely control their disease during pregnancy.

If a patient becomes pregnant on DMARD therapy (other than those listed as safe below) contact the rheumatology department.

Some centres offer combined obstetric and rheumatology clinics for pre conception advice. For more complex cases, patients can be referred by their rheumatology team.

In general, medications considered safe in preconception and throughout pregnancy include:

Hydroxychloroquine
Sulfasalazine with 5mg folic acid (not co-prescribed outside pregnancy)
Azathioprine (<2mg/kg/day)
Ciclosporin and tacrolimus
Corticosteroids

Medications contraindicated in pregnancy:

Methotrexate (stop 3 months prior to conception, folic acid 5mg throughout pregnancy)
Mycophenolate mofetil (stop 6 weeks prior to conception)
Leflunomide - leflunomide stays in the body for a long time. If considering pregnancy, or if conception occurs while taking leflunomide contact Rheumatology as a cholestyramine washout can be performed (8g TDS for 11 days)

Most new drugs (biologics, JAK-STAT inhibitors) are not compatible with pregnancy (check BSR guideline referenced below for further details). Anti-TNFs are the exception:

Infliximab - stop at 16th week of pregnancy
Etanercept and Adalimumab - stop at end of second trimester
Certolizumab - safe throughout pregnancy

References

BSR guidelines - https://www.rheumatology.org.uk/practice-quality/guidelines

DMARDs
Biological DMARD safety
Pregnancy and breastfeeding (https://www.rheumatology.org.uk/practice-quality/guidelines)

Monoclonal antibodies

In Rheumatology, monoclonal antibodies (mAb) are used to:

Target pro-inflammatory cytokines or growth factors
Deplete a pathogenic cell subset or
Modulate cell to cell interactions in the immune system.

Drug Name	Target	Structure	Licensed Indication(s)	Route of administration
Abatacept	CD80/CD86	Fusion protein of CTLA4 extracellular domain and human IgG1 Fc	RA, JIA	SC; IV
Adalimumab	TNF	Fully human mAb	RA; JIA; AS; PsA;	SC
Alemtuzumab	CD52	Humanised mAb	MS	IV
Anakinra	IL-1	Recombinant human IL-1 receptor antagonist	RA; CAPS; Still’s disease	SC
Belimumab	Blys	Fully human mAb	SLE	IV, SC
Canakinumab	IL-1β	Fully human mAb	Gout; JIA (systemic); CAPS; Still’s disease	SC
Certolizumab Pegol	TNF	Humanised mAb Fab' fragment linked to PEG	RA; AS; PsA;	SC
Denosumab	RANKL	Fully human mAb	Osteoporosis	SC
Etanercept	TNF	Fusion protein of human p75 TNF receptor EC domain and human IgG1 Fc	RA; AS; JIA; PsA;	SC
Golimumab	TNF	Fully human mAb	RA; AS; PsA	SC
Infliximab	TNF	Chimeric mAb	RA; PsA; AS	IV
Ixekizumab	IL-17A (both IL-17A and IL17A/F)	Humanized mAb	PsA	SC
Rituximab	CD20	Chimeric mAb	RA; ANCA +ve vasculitis; SLE	IV
Sarilumab	IL-6 receptor	Fully human mAb	RA	SC
Secukinumab	IL-17A	Fully human mAb	PsA, AS	SC
Tocilizumab	IL-6 receptor	Humanised mAb	RA; JIA; GCA	IV, SC
Ustekinumab	IL-12 & IL-23 (p40 subunit)	Fully human mAb	Ps, PsA	SC

Abbreviations: CD, cluster of differentiation; CTLA4, cytotoxic T-lymphocyte associated protein 4; EC, extracellular; Ig, immunoglobulin; Fc, fragment crystallisable; JIA juvenile idiopathic arthritis; SC, sub-cutaneous; IV, intravenous; TNF, tumour necrosis factor; mAb, monoclonal antibody; AS, ankylosing spondylitis; PsA, psoriatic arthritis; IL, interleukin; CAPS, cryopyrin-associated periodic syndrome; BLyS, B-lymphocyte stimulator; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis ; Fab, fragment antigen binding; PEG, polyethylene glycol; RANKL, receptor activator of nuclear factor kappa-B ligand

DMARDs disease modifying anti-rheumatic drugs

Drug Name	Target	Indication(s)	Route of administration
Azathioprine	Converted to 6-MP. Decreases the de novo synthesis of purine nucleotides, reducing synthesis of DNA, RNA and proteins.	RA; SLE; myositis; ANCA vasculitis	PO
Hydroxychloroquine	Anti-malarial – precise action not known	RA; SLE	PO
Leflunomide	Active metabolite teriflunomide decreases synthesis of pyrimidines. Leads to arrest of lymphocyte cell division.	RA; PsA	PO
Methotrexate	Methotrexate enters cells and undergoes polyglutamation with multiple effects on the immune system	RA; JIA; PsA; peripheral involvement of seronegative arthritis; vasculitis; myositis	PO; S/C
Mycophenolate mofetil	Reversible inhibitor of IMPDH (inosine-5’-monophosphate dehydrogenase) necessary for purine synthesis. Inhibits lymphocyte proliferation and migration.	RA; SLE; myositis; ANCA vasculitis	PO
Sulfasalazine	2 component drug: sulfapyridine (antimicrobial) 5-aminosalyicyclic acid (anti-inflammatory)	RA; JIA; PsA; peripheral involvement of seronegative arthritis	PO
JAK inhibitors
Barictinib	JAK1, JAK2	RA	PO
Filgotinib	JAK1	RA	PO
Tofacitinib	JAK1, JAK3	RA	PO

Abbreviations: JAK, janus kinase; JIA juvenile idiopathic arthritis; SC, sub-cutaneous; PO, per os (by mouth); PsA, psoriatic arthritis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus

Vaccines

COVID 19

All patients should receive one of the currently available covid 19 vaccinations Pfizer/BioNTech COVID-19 mRNA Vaccine BNT162b2 or Oxford/Astra Zeneca ChAdOx1 nCoV-2019.

These are not live vaccinations.

They should be offered to patients regardless of their Rheumatology diagnosis of treatment regime, provided there are no contraindications.

Detailed information about the efficacy in the immunocompromised is not yet available.

Patients should not stop their immunosuppression prior to vaccination.

Shared decision making is required to balance any delay in starting immunosuppression to enable vaccination to take place. Those patients planned to receive immunosuppressive therapy should be considered for covid 19 vaccination prior to commencing therapy (ideally at least two weeks before). For maximum benefit they should be offered the second dose at the recommended minimum interval for that vaccine (three or four weeks from the first dose) so that the second dose is not given once immunosuppression has commenced.

Vaccinations for those on immunosuppressive treatment

This topic is comprehensively covered in ‘The Green Book’

Public Health England provide guidelines on vaccinations for patients on immunosuppressive therapies.

Broad principles for all patients:

Influenza vaccination should be offered yearly
Pneumococcal boosted vaccination should be offered every five years
Human papilloma vaccination is recommended for those young women who have already received part of the vaccination schedule.
Live attenuated vaccines should not be given to individuals who are immunosuppressed
Inactivated vaccines should ideally be given at least two weeks before starting immunosuppression to achieve a good immune response, though this is often not possible.

Live vaccines (e.g. herpes zoster vaccination, rabies, yellow fever, MMR, BCG vaccination)

These can replicate after administration so should not be given to significantly immunosuppressed individuals:

If required they should be given at least 4 weeks before commencing immunosuppressive treatment or six months after stopping

Patients on the following medications are NOT considered to be significantly immunosuppressed in this setting, and so can receive live vaccinations:

Low dose steroids ( <20mg/day pred for 14 days)
Methotrexate < 25mg/wk
Azathioprine <3mg/kg/day
Sulfasalazine any dose
Hydroxychloroquine any dose

Consider precautions if giving live attenuated vaccines to close contacts of immunosuppressed individuals e.g rotavirus to babies.

Vaccinations prior to starting a biologic drug

Hepatitis B vaccination

Inactivated vaccine
Offer first vaccine to those with ongoing risk factors for HBV prior to starting anti-TNF due to the suggestion that anti-TNFs may modulate the humoral response.

Herpes zoster vaccination

Live attenuated vaccine
Currently given as part of national vaccination programme for over 70s
Zostavax is not licensed for people under the age of 50

Varicella Zoster vaccine

Live attenuated vaccine
Offered to those without a positive history of chicken pox and a negative varicella zoster virus antibody test, without contraindications to vaccination
Vaccination of healthy, close household contacts is recommended

Other live attenuated vaccines

If required, should be given, if no other contraindications, at least 2 weeks (ideally 4 weeks) before starting an anti-TNF treatment.

References

ARMA http://arma.uk.net/covid-19-vaccination-and-msk/

The Green Book https://www.gov.uk/government/collections/immunisation-against-infectious-disease-the-green-book

BSR https://www.rheumatology.org.uk/practice-quality/guidelines

Chicken pox exposure

The principle of post exposure management is to protect those at high risk of suffering from severe varicella infection. Discuss with Virology/Infectious Diseases.

The requirement for varicella zoster immunoglobulin (VZIG) in an immunosuppressed individual who has not had chickenpox or vaccination is determined by:

1) The length and type of contact

Significant exposure includes: An index case with chickenpox, disseminated zoster, with exposed zoster lesions or an immunocompromised index case with localised zoster at any location

2) The presence of antibodies to VZ virus

Where possible test irrespective of history, but do not delay treatment

VZVIG reduces the development of clinical chicken pox but patients still need to watch out for signs and symptoms. If these develop they should be treated promptly with aciclovir.

Reference

The Green Book https://www.gov.uk/government/collections/immunisation-against-infectious-disease-the-green-book