Checkpoint inhibitors and rheumatic side effects (irAE) 5/5 (2)

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

Definition

Checkpoint inhibitors (immunologic check-point inhibitors, ICI, control point inhibitors) are used in the treatment of cancer increasingly. New drugs within this group are being introduced, the indications are being expanded and more cancers are being treated. New data show that over 40% of cancer cases can be considered for such treatment (Haslam A, 2019). The use of checkpoint inhibitors will become more routine in the years to come. One drawback is that rheumatic symptoms are topical side effects. These typically occur a few weeks after starting treatment.

Checkpoint inhibitors work via immune system. Side effects that indicate a reaction from the immune system are common, but rarely serious. Skin symptoms often occur, such as the development or worsening of psoriasis, gastrointestinal symptoms, and hormonal disorders 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. The rheumatologist's task is to map rheumatic symptoms and contribute to the treatment in collaboration between the oncologist (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

Occurrence of rheumatic side effects of checkpoint inhibitors

Data so far indicate that 10-20% get immune-related side effects and approx. 5-10% get rheumatic symptoms and / or disease related to this cancer treatment. Joint and muscle pain are most common. Arthritis (arthritis) occurs in 3-7% (Calabrese L, 2020). The incidence is slightly higher (30%?) When combination treatment for cancer is given (anti CTLA4 + anti Pd1). Most symptoms (80%) return spontaneously within 1-3 months of starting cancer treatment. Less than 10% need treatment in addition to corticosteroids (prednisolone) for a limited period. 

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.

Other autoimmune side effects

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.

Examinations

  • 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-steroidal anti-rheumatic drugs) such as ibuprofen, naproxen diclofenac and others against joint and muscle pain
  • Other types pain medications
  • Cortisone in joints if necessary (arthritis) via rheumatologist
  • Prednisone in a dose of 10-20 mg / day is often effective against these joint and muscle inflammations. Higher dose may be required for vasculitis (rare). Usually 4-6 weeks of treatment is initially intended. High dose Prednisolone (0,5-1mg / kg / day) if severe symptoms. It is desirable to evaluate by a rheumatologist before starting prednisolone treatment
  • If not sufficient Prednisolone (low dose and limited duration of treatment)

Prognosis

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 *

Literature


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