Original Editor - Temitope Olowoyeye

Top Contributors - Temitope Olowoyeye, Kirenga Bamurange Liliane and Vidya Acharya  

Introduction[edit | edit source]

Cryoglobulinemia is an autoimmune disorder that is characterised by the persistent presence of a cryoglobulin (Igs) in the serum.[1] [2] Cryoglobulins are proteins that precipitate from an individual’s serum or plasma at temperatures lower than 37 °C, leading to cryoprecipitate. They can be a mixture of immunoglobulin (Ig) and complement components or immunoglobulins alone. Cryoglobulins, which accumulate in blood vessels, can cause endothelial injury and end-organ damage, resulting in cryoglobulinemia.[1][2] The disease mainly affects small to medium-sized blood vessels[3] and causes vasculitis, which leads to a systemic inflammatory syndrome characterised by fatigue, arthralgia, purpura, neuropathy, and glomerulonephritis. It should be suspected in patients with skin ulcers, arthralgia, glomerulonephritis, neuropathy, and purpura.[1][2]

According to Brouet’s classification, cryoglobulins are classified into three types: Type I, Type II, and Type III, on the basis of their immunoglobin (Ig) composition.[2][4][5] Cryoglobulinemia is a rare condition affecting 1 in 100,000 people, with about 15%-20% of HIV-infected individuals, 40-65% of Hepatitis C-infected patients, and 64% of HIV/HepC coinfected individuals. Type 1 cryoglobulin patients make up 5%-25% of cases, according to the available studies.[2]

  1. Type I cryoglobulinemia: This is characterised by a monoclonal immunoglobulin (usually IgM) or a single monoclonal immunoglobulin (most commonly immunoglobulin M (IgM), rarely IgG or IgA). It is often associated with lymphoproliferative disorders like Waldenström macroglobulinemia, multiple myeloma, chronic lymphocytic leukaemia, or protein-secreting monoclonal gammopathies like monoclonal gammopathy of undetermined significance (MGUS).[2] [4][5]
  2. Type II cryoglobulinemia: In this type, a combination of monoclonal antibodies (usually IgM with rheumatoid factor activity) forms immune complexes with polyclonal IgG. It is commonly associated with Hepatitis C virus (HCV) infection, mixed cryoglobulinemia syndrome, hepatitis B virus (HBV), HIV, Sjögren's syndrome, and lymphoproliferative disorders.[2][4][5]
  3. Type III cryoglobulinemia: This type involves polyclonal IgM and IgG-forming immune complexes with no monoclonal immunoglobulin. Type III cryoglobulinemia is frequently seen in patients with autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis.[5]

Pathophysiology[edit | edit source]

Cryoglobulinemia is a multifactorial disease characterised by the production of abnormal immunoglobulins by B lymphocytes or plasma cells, which can form immune complexes with antigens, particularly at lower temperatures. Mono-, oligo-, or polyclonal immunoglobulin synthesis is increased by lymphoproliferation and chronic immunological activation, which results in the development of cryoglobulins and antigen-antibody complexes.[2] [5]Accumulation of these complexes occurs due to insufficient clearance which deposits them in small blood vessels, particularly in the skin, kidneys, and peripheral nerves, causing inflammation and tissue damage.

Clinical Presentation[edit | edit source]

The clinical course of cryoglobulinemia is unpredictable. There are periods of remission and exacerbations. Patients may exhibit a wide range of symptoms. Common clinical manifestations include:[2][6]

  1. Vasomotor: Raynaud's Phenomenon and Acroyanosis[6]
  2. Skin Involvement: Palpable purpura (purplish skin lesions), livedo reticularis (mottled, net-like pattern on the skin), and ulcerations are frequently observed.[6][7]
  3. Arthralgia and Myalgia: Patients often complain of joint and muscle pain.[6][7]
  4. Neurologic Symptoms: Peripheral neuropathy with sensory and motor deficits can occur due to nerve ischemia caused by cryoglobulin deposition.[7][5]
  5. Gastrointestinal Manifestations: Abdominal pain, gastrointestinal bleeding, and bowel ischemia have been reported.
  6. Systemic Symptoms: Fatigue, weakness, and fever may be present, reflecting the systemic nature of the disease.[6][7][8]
  7. Renal Involvement: Glomerulonephritis can occur, leading to proteinuria and hematuria. In severe cases, renal failure may develop.[7][8]

Diagnosis[edit | edit source]

The diagnosis of cryoglobulinemia syndrome is predominantly based on the laboratory demonstration of serum cryoglobulins.The most predictive Test for cryoglobulinemia is the measurement of cryoglobulin combined with a low C4 complement level, which is l of cryoglobulinemia syndromes.[2][8]Other tests are immunochemical analysis, urinalysis, complement serum analysis, rheumatoid factor levels, viral serologies, and analysis of acute-phase reactants. Also, biopsy of organs that are affected by the disease.[2]

Management[edit | edit source]

Cryoglobulinemia can be challenging to treat due to its diverse underlying states, and asymptomatic patients typically do not require treatment. NSAIDs are often prescribed to manage mild symptoms like fatigue, arthralgia, and myalgia.[2] [5]However, patients with moderate to severe symptoms, such as progressive renal failure, necrosis of the distal extremities, or uncontrolled neuropathy, require aggressive therapies like plasmapheresis and/or steroid/cytotoxic drugs. Plasmapheresis is typically required three times per week for three weeks.[1][5] However, a recent study suggests unclear protocols and quantitative outcomes.[5]

For patients with type I cryoglobulinemia it is important to treat hematological malignancies or lymphoproliferative disorders, chemotherapy and radiation therapy are recommended.

Implications For Rehabilitation[edit | edit source]

Rehabilitation therapists often work as part of a multidisciplinary team in the management of cryoglobulinemia to ensure that the patient's treatment plan addresses both the underlying causes of cryoglobulinemia and its physical manifestations, such as joint pain, joint imobility, swelling, stiffness, problems with balance, and coordination.

Rehabilitation therapist can employ various modalities such as manual therapy, therapeutic exercises, and electrotherapy to alleviate pain and improve joint mobility reducing the impact of pain on daily activities. Specialized rehabilitation programs that focus on sensory re-education and motor retraining to improve balance, coordination, and proprioception while minimizing the risk of falls and injuries.

It is of importance for Rehabilitation therapists to know that the use of cryotherapy in this group of patients is highly contraindicated. Since cryoglobulinemia can be triggered or exacerbated by cold exposure,[9] patients should be educated on how to protect themselves from cold temperatures. This may include recommending appropriate clothing, advising on cold weather precautions, and teaching techniques to warm up and maintain body temperature during physical activities.

Resources[edit | edit source]

References[edit | edit source]

  1. 1.0 1.1 1.2 1.3 Naciri Bennani H, Banza AT, Terrec F, Noble J, Jouve T, Motte L, Malvezzi P, Rostaing L. Cryoglobulinemia and double‐filtration plasmapheresis: Personal experience and literature review. Therapeutic Apheresis and Dialysis. 2023 Feb;27(1):159-69.
  2. 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 Bhandari J, Awais M, Aeddula NR. Cryoglobulinemia.reasure Island (FL): StatPearls Publishing; 2023 Jan-.
  3. Muchtar E, Magen H, Gertz MA. How I treat cryoglobulinemia. Blood, The Journal of the American Society of Hematology. 2017 Jan 19;129(3):289-98.
  4. 4.0 4.1 4.2 Roccatello D, Saadoun D, Ramos-Casals M, Tzioufas AG, Fervenza FC, Cacoub P, Zignego AL, Ferri C. Cryoglobulinaemia. Nature Reviews Disease primers. 2018 Aug 2;4(1):11.
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Takada S, Shimizu T, Hadano Y, Matsumoto K, Kataoka Y, Arima Y, Inoue T, Sorano S. Cryoglobulinemia. Molecular medicine reports. 2012 Jul 1;6(1):3-8.
  6. 6.0 6.1 6.2 6.3 6.4 Liou YT, Huang JL, Ou LS, Lin YH, Yu KH, Luo SF, Ho HH, Liou LB, Yeh KW. Comparison of cryoglobulinemia in children and adults. Journal of Microbiology, Immunology and Infection. 2013 Feb 1;46(1):59-64.
  7. 7.0 7.1 7.2 7.3 7.4 Sidana S, Rajkumar SV, Dispenzieri A, Lacy MQ, Gertz MA, Buadi FK, Hayman SR, Dingli D, Kapoor P, Gonsalves WI, Go RS. Clinical presentation and outcomes of patients with type 1 monoclonal cryoglobulinemia. American journal of hematology. 2017 Jul;92(7):668-73.
  8. 8.0 8.1 8.2 Desbois AC, Cacoub P, Saadoun D. Cryoglobulinemia: an update in 2019. Joint bone spine. 2019 Nov 1;86(6):707-13.
  9. Prohaska J, Jan AH. Cryotherapy. PMID: 29493944.