Checkpoint inhibitors and rheumatic side effects (irAE) 5/5 (3)

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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. As of 2019, over 40% of cancer cases were assessed for such treatment (reference: Haslam A, 2019). A disadvantage is that rheumatic symptoms such as side effects can occur a few weeks after starting treatment. Usually, however, the cancer treatment can continue, despite rheumatic side effects.

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).

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 who are to be perceived as "strangers" and rendered harmless before they develop disease. The body's "checkpoint molecules" are usually important in this process. Untreated, however, cancer cells use the checkpoints to protect themselves against attacks from the immune system, so that the cancer develops. Drugs in the form of checkpoint inhibitors make the cancer cells available to our own immune system so that it can destroy them (via T cell activation). A disadvantage is that the immune system then becomes more susceptible to by mistake also attacking its own, healthy tissue and thus triggering 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 (not complete list)

Rheumatic symptoms of checkpoint inhibitors

About 10-20% get immune-related side effects and 5-10% get rheumatic symptoms and / or disease related to this cancer treatment. Joint- og muscle aches is most common. Arthritis (arthritis) occurs in 3-7% (Calabrese L, 2020). The incidence is slightly higher with combination treatment for cancer (anti CTLA4 + anti Pd1). Most symptoms (80%) return spontaneously within 1-3 months after the start of cancer treatment. Less than 10% need treatment in addition to corticosteroids (prednisolone) for a limited period. NOTE! Always check that the symptoms are not due to cancerous growth / metastasis.

Rheumatological, autoimmune side effects of checkpoint inhibitors

Side effects in some cases lead to disease images that are reminiscent Systemic connective tissue diseases:, vasculitides or others Autoimmune diseases, but are most often still not completely typical (Reference: * Le Burel EJC 82 (2017) 34-44; Abdel-Wahab; 2016)

Other autoimmune side effects

Relapse of known rheumatic disease

If there is an autoimmune rheumatic disease such as arthritis (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

Disease history covers current symptoms and prior cancer treatment. Rheumatological disease history and Clinical Examination of joints, back, blood vessels, muscles and muscle strength.

Clinical examines joints, muscles, skin, mucous membranes, thyroid, salivary glands, temporal artery and nervous system. In case of dryness in mucous membranes, measurement of tear and saliva production (Schirmer test, sialometry) for dryness is

Blood tests which may be relevant: SR (lowering reaction), CRP (c-reactive protein), cell counts (Hemoglobin, leukocytes, platelets), liver and kidney function tests (ALT, AST, g-Gt, LD, Creatinine, GFR), CK (creatine kinase), troponin-T on suspicion of myocarditis (myocarditis), free T4, TSH, prolactin and other hormones on suspicion of pituitary failure, ACPA (anti-CCP), RF (rheumatoid factor), ANA (antinuclear antibody), possibly with ENA and subgroups (SSA / Ro, DNA, etc.). Myositis-specific antibody in case of myositis suspicion, ANCA (anti-cytoplasmic antibody). PR3 and MPO, antibody to paraneoplastic diseases can be consideredHLA-B27 if Inflammatory back pain.

Urin test (erythrocytes, proteins, possible protein / creatinine ratio and microscopy)

Stool sample (FeCal test) on calprotectin on suspicion of colitis (colitis)

ultrasound of the heart (echocardiography) in case of suspected myocarditis

MRI of (thigh) muscles and EMG are assessed if suspected of myositis

ECG

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 rheumatic side effects are transient or treatable so that cancer treatment can continue. The course of the cancer is thus not negatively affected. Over 90% get rid of the rheumatic side effects over time *.

Literature


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