Checkpoint inhibitors and rheumatic side effects (irAE) 5/5 (1)

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Blue fingers during treatment with checkpoint inhibitors against malignant melanoma; Gamichler C, BMC Cancer (2017). CC BY 4.0


Checkpoint inhibitors (immunologic check-point inhibitors, ICI, control point inhibitors) are used in the treatment of cancer increasingly. New drugs within this group are coming, the indications are expanded and several cancers are being treated. The use of checkpoint inhibitors will be more routine in the years to come. Rheumatic symptoms may occur a few weeks after the start of treatment.

Checkpoint inhibitors work via immune system. Side effects suggestive of immune system response are common, but rarely severe. Symptoms often occur from skin, such as the development or exacerbation of psoriasis, gastrointestinal symptoms and hormonal disease such as metabolic disease. But also rheumatic symptoms like joint- og muscle aches, less often arthritis , muscle inflammation (Myositis og Polymyalgia rheumatica-like), and others occur. It will be the rheumatologist's task to map rheumatic symptoms and contribute to the treatment in collaboration between cancer patients (oncologist).

There are (per 2019) few research studies, so the incidence and consequence of rheumatic side effects of checkpoint inhibitors is not well mapped. Experience with the treatment of side effects caused by checkpoint inhibitors remains in the initial phase.

Mechanism of action

The checkpoint inhibitor nivolumab works by inhibiting binding between T cell and tumor cell; Guo L, J cancer 2017, CC BY-NC 4.0

Our immune system must separate normal cells from cancer cells which should be perceived as "strangers" and destroyed before they develop disease. «Checkpoint» molecules prevent the immune system from attacking the body's own cells. Cancer cells, however, use checkpoints to protect against immune system attacks, so that cancer develops. Medication in the form of checkpoint inhibitors make the cancer cells accessible to our own immune system so that cancer cells are destroyed (via T cell activation). One disadvantage is that the immune system by mistake becomes more susceptible to attacking own healthy tissues, thus trigger autoimmune phenomena and Autoimmune disease.

Some checkpoint inhibitors

CTLA-4 inhibitor (CTLA-4 = Cytogenic T-lymphocyte-associated protein 4)

  • Ipilimumab (Yervoy)

PD-1 inhibitors (PD-1 = Programmed cell death protein 1)

  • Pembrolizumab (Keytruda)
  • Nivolumab (Opdivo)

PD-L1 Inhibitors (Ligand Inhibitors)

  • Atezolizumab (Tecentriq)
  • Avelumab (Bavenico)
  • Durvalumab (Imfinzi)

Cancer that (in some cases) can be treated with checkpoint inhibitors

Rheumatological, autoimmune side effects of checkpoint inhibitors

When checkpoint inhibitors open the immune system to attack cancer cells, the risk occurs that the immune system accidentally also damaging healthy cells in different parts of the body. Thus, rheumatic pain and inflammation can occur (immune-related adverse events, IrAE). These reactions, in some cases, lead to diseases like Systemic connective tissue diseases:, vasculitides or others Autoimmune diseases, but are usually not quite typical.

The incidence is 5-10% and higher (30%?) when combination therapy for cancer is given (anti CTLA4 + anti Pd1). Most (80%) Get Symptoms During 1-XNUM months after Cancer Treatment starts

Other autoimmune side effects

Occurrence of rheumatic side effects of checkpoint inhibitors

Data to date indicate that 5-10% receive rheumatic symptoms and / or disease related to this cancer treatment. Joint and muscle pain are most common. Arthritis (joint inflammation) occurs in 3-4%.

Residue of known rheumatic disease

If there is an autoimmune rheumatic disease such as rheumatoid arthritis, Psoriatic arthritis, systemic connective tissue disease or Vasculitis, the disease can flare up during cancer treatment with checkpoint inhibitors. One assumes that approximately one in three experiences this.


  • Rheumatological disease history and Clinical Examination of joints, back, blood vessels, muscles and muscle strength
  • Skin, mucous membranes, thyroid, salivary glands, temporal artery, nervous system
  • Measurement of tear and saliva production (Schirmer's test, sialometry) in dryness conditions
  • Blood tests
    • ESR (sedimentation rate)
    • CRP (c-reactive protein)
    • Cell counts (Hemoglobin, leukocytes, platelets)
    • Liver and renal function tests (ALAT, ASAT, g-Gt, LD, Creatinine, GFR)
    • CK (creatine kinase)
    • Troponin-T suspected of myocarditis
    • Free T4, TSH
    • Prolactin and other hormones in suspected pituitary failure
    • ACPA (anti-CCP)
    • RF (rheumatoid factor)
    • ANA (antinuclear antibody), possibly with ENA and subgroups (SSA / Ro, DNA, etc.). Myosititis-specific antibodies in myositis suspicion
    • ANCA (anti-cytoplasmic antibody). PR3 and MPO
    • Antibodies to paraneoplastic diseases can be considered
    • HLA-B27 if Inflammatory back pain
  • Urine test (erythrocytes, proteins, possibly protein / creatinine ratio and microscopy)
  • Stool test (FeCal test) on calprotectin in case of suspected colon inflammation
  • ECG and ultrasound of the heart (echocardiography) on suspicion of myocarditis
  • MRI of (thigh) muscles and EMG are assessed if suspected of myositis
  • NB Always check that the symptoms are caused by cancerous tumor / metastasis!

Treatment of rheumatic side effects of checkpoint inhibitors

First priority is that the cancer disease gets optimal treatment

  • The side effects are not a sign that the cancer treatment does not work (possibly with people with autoimmune side effects having the best treatment effect)
  • Usually it is not necessary to end the cancer treatment with checkpoint inhibitors
  • Not everyone needs medication
    • Customized physiotherapy may be useful, optionally in combination with medication
  • Some anti-rheumatic drugs may be unfavorable
    • They can inhibit healing
    • They are not always tolerated with the cancer medicine or
    • They can not be used due to prior treatment, other illness or organ damage
  • Rheumatic diseases that exist before the cancer treatment starts can worsen. However, cancer treatment can still continue most often (see medication / measures below)
  • Collaboration between cancer therapists (oncologists) and rheumatologists is important

Some medications should be considered

  • Paracetamol og / eller NSAIDs (Non-Steroid Anti-Rheumatic Drugs) such as ibuprofen, naproxen diclofenac and others against joint and muscle pain
  • Other types pain medications
  • Referral to rheumatologist
    • The rheumatologist would prefer to investigate before Prednisolone treatment starts
  • Cortisone in joints when needed (arthritis)
  • Prednisone dose 10-20 mg / day is often effective against these joint and muscle inflammations. Higher doses may be required for vasculitis (rare). Usually, 4-6 weeks of treatment is intended. High dose prednisolone (0,5-1mg / kg / day) if severe symptoms
  • If not sufficient Prednisolone (low dose and limited duration of treatment)


  • Most people with rheumatic side effects have good prognosis
    • Short-term anti-rheumatic treatment is usually sufficient (please see above)
    • The course of the cancer is usually not adversely affected
    • 93% get rid of rheumatic side effects over time *


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