‘To treat or not to treat’: raising awareness on the effects of graft versus host disease drugs on musculoskeletal system

With an increase in the rate of survival of hematopoietic cell transplant (HCT) patients, the burden of late post-transplant complications also has increased tremendously. Unlike acute graft-versus-host-disease (GVHD), chronic GVHD and its complications may present in a variety of manifestations including scleroderma, fasciitis, polymyositis, myopathies, Sjögren’s syndrome, neurological sequelae, primary biliary cirrhosis, vaginal GVHD, wasting syndrome, genital GVHD, bronchiolitis obliterans, immune cytopenias, and chronic immunodeficiency [1, 2].

From the functional quality of life point of view, the main aim of the management is to help improve overall function, joint range of motion, prevent contractures, aid the bone matrix, improve tissue-healing process, improve quality of life, and reduce pain. Currently, the main complimentary choice of therapy for managing musculoskeletal manifestation (MSK) of chronic GVHD seems to be largely focused on exercise therapy [3].

Owing to the complexity of the GVHD disease, the patients are often taking several medications ranging from immunosuppressive drugs, antibiotics, anti-inflammatory, corticosteroids, and analgesics [4]. Post HCT, it is vital that the rehabilitation team are aware of the key drugs, their interaction profiles and adverse effects since many drugs are known to have a negative influence on the MSK performance of the patients. The current paper outlines some of the most commonly used drugs and their side effects from MSK point of view.

Calcineurin inhibitors

The calcineurin inhibitors (CNI), i.e., cyclosporine A, and tacrolimus are powerful immunosuppressive agents aimed for prevention of GVHD in patients receiving allogeneic hematopoietic HCT [5]. Several studies have reported dose-related varying adverse effects on the MSK from cyclosporine (Table 1). Isolated musculoskeletal pain in the ankles, feet, knees, wrists, shoulders, elbows, or metacarpophalangeal joints, ‘leg bone pain syndrome’ have been reported with CNI’s and in some cases, patients having to use crutches to walk have been observed [6, 7]. Interestingly, in one of the case report, once tacrolimus was suspended owing to the suspicion of CNI induced pain syndrome (alternatively mycophenolic acid and steroid therapy were commenced), a subsequent profound improvement in the clinical picture was observed. From the above few cases, it is evident that the role of physical therapy [PT] would have been limited in such patients, but the knowledge about the drugs and their adverse effects would have helped the therapist direct the patient to the right care resulting in early intervention, thereby reducing the burden of the disease on the patient.

Table 1 Cyclosporine drugs effect on MSK related symptoms and the resolving factors study

Systemic corticosteroids

Topical steroid alone is generally indicated for Grade I aGVHD, and systemic corticosteroids remain the mainstay of first-line treatment in grade II–IV aGVHD starting with prednisolone or Methylprednisolone [8]. If the GVHD symptoms are worsening in any organ over 3 days of treatment or there is no response to steroid therapy in 5–14 days, secondary line treatment is usually considered [9].

There are multiple side effects of the use of steroids such as immunosuppression, osteopenia, oedema, muscle atrophy, skin atrophy, and impaired wound healing (long-term use) [10]. Vertebral fractures because of increased osteocyte and osteoblast death by apoptosis and inhibition of osteoblast generation is another important feature which the rehabilitation specialists need to be aware of where a patient might complain of non-resolving persisting back pain [11].  Lastly, avascular necrosis is one of the most debilitating adverse effects, which typically happens within a couple of years of HCT [12].

mTOR inhibitors

Dose-dependent sirolimus has been associated with side effects like disabling joint pain and oedema particularly in the legs [13, 14] and in some worse cases leading to knee-joint necrosis requiring knee replacement [15].

Proteasome inhibitors

Proteasome inhibition with agents, such as bortezomib and ixazomib, have assumed a central role in the management of multiple myeloma but has been used for both prevention and treatment of cGVHD [16]. The most common adverse effects of bortezomib (a proteasome inhibitor) from MSK point of view include:

Dose-dependent bortezomib-induced peripheral neuropathy affecting the hands and legs with burning and tingling pain in the legs has been reported for between 55 to 70% of the patients in various studies [17, 18] and the author’s placing emphasis on the importance of knowledge and monitoring of any new or worsening symptoms or signs of neuropathy in patients on bortezomib therapy.

Caution must be exerted by the PT with patients under bortezomib when administering rehabilitation sessions as patients treated with bortezomib have shown to have a reduction in the platelet count by an average of 60% during the first 14 days of treatment and can take up to 21 days to recover [19]. Several studies have suggested that reduced platelet count is a contraindication or precaution for patients performing exercises [20].

JAK inhibitors

Ruxolitinib is an oral inhibitor of the JAK-1 and JAK-2 tyrosine kinases. Some of the common side effects seen in patients included fatigue, dizziness and muscle cramps [21] and one study reported a high incidence of anaemia and worsening of cytopenia [22]. However, it must be noted that these side effects were only at Grade I–II and short-lived, and cytopenia as a result of ruxolitinib was treatable with dose reduction and/or interruptions [23].

Tumor necrosis factor (TNF) alpha-blockers (etanercept, infliximab, and adalimumab)

Some of the side effects related to patient’s on TNF drugs include neurological problems, new onset or exacerbation of central nervous system demyelinating disorders [24], new onset or exacerbation of seizure disorders, lupus [25], Guillain-Barre´ syndrome [26], paresis of the left facial nerve [27]

BTK inhibitors

Ibrutinib is a BTK inhibitor, which was recently approved for use in steroid-refractory cGVHD by the United States Food and Drug Administration. Although there is a paucity of data on ibrutinib’s direct effect on MSK in GVHD patients, it is well known that this drug can result in muscle cramps and myalgias [28]. Recently, spontaneous muscle haemorrhage was also reported owing to its use [29].

Conclusions

It is imperative that transplant clinicians and rehabilitation professionals (particularly physical therapists) be familiar with the adverse effect profiles of common medications used in the treatment of GVHD, especially which impact the musculoskeletal function and overall rehabilitation. Guidelines are urgently needed to address many issues pertaining to PT in GVHD patients including platelet count cutoff, steroid myopathy, neutropenic risks, and neuropathy management.

References

  1. 1.

    Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:215–33.

    Article  PubMed  CAS  Google Scholar 

  2. 2.

    Flowers MED, Vogelsang GB. Clinical manifestations and natural history. In: Vogelsang GB, Pavletic SZ (eds). Chronic Graft Versus Host Disease: Interdisciplinary Management. New York, NY, USA: Cambridge University Press; 2009. pp 56–69.

    Google Scholar 

  3. 3.

    Mohammed J, Savani B, El-Jawahri A, Vanderklish J, Cheville A, Hashmi S. Is there any role for physical therapy in chronic GvHD?. Bone Marrow Transplant. 2018;53:22–28.

    Article  PubMed  CAS  Google Scholar 

  4. 4.

    Holler E. Risk assessment in haematopoietic stem cell transplantation: GvHD prevention and treatment. Best Pract Res Clin Haematol. 2007;20:281–94.

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Fujii N, Ikeda K, Koyama M, Aoyama K, Masunari T, Kondo E, et al. Calcineurininhibitor—induced irreversible neuropathic pain after allogeneic hematopoietic stem cell transplantatioan. Int J Hematol. 2006;83:459–61.

    Article  PubMed  Google Scholar 

  6. 6.

    Collini A, De Bartolomeis C, Barni R, Ruggieri G, Bernini M, Carmellini M. Calcineurin-inhibitor induced pain syndrome after organ transplantation. Kidney Int. 2006;70:1367–70.

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Naredo SE, Balsa CA, Sanz GA, Pantoja ZL, Martín ME, Gijón BJ. Leg bone pain syndrome due to cyclosporine in a renal transplant patient. Clin Exp Rheumatol. 1993;12:653–6.

    Google Scholar 

  8. 8.

    Van Lint MT, Milone G, Leotta S, Uderzo C, Scime R, Dallorso S, et al. Treatment of acute graft-versus-host disease with prednisolone: significant survival advantage for day+ 5 responders and no advantage for nonresponders receiving anti–thymocyte globulin. Blood. 2006;107:4177–81.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Dignan FL, Amrolia P, Clark A, Cornish J, Jackson G, Mahendra P, et al. Diagnosis and management of chronic graft‐versus‐host disease. Br J Haematol. 2012;158:46–61.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Gergis U, Markey K, Greene J, Kharfan-Dabaja M, Field T, Wetzstein G, et al. Voriconazole provides effective prophylaxis for invasive fungal infection in patients receiving glucocorticoid therapy for GVHD. Bone Marrow Transplant. 2010;45:662–7.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Balasubramanian A, Wade SW, Adler RA, Lin CJ, Maricic M, O’Malley CD, et al. Glucocorticoid exposure and fracture risk in patients with new-onset rheumatoid arthritis. Osteoporos Int. 2016;27:3239–49.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Li X, Brazauskas R, Wang Z, Al-Seraihy A, Baker KS, Cahn JY, et al. Avascular necrosis of bone after allogeneic hematopoietic cell transplantation in children and adolescents. Biol Blood Marrow Transplant. 2014;20:587–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. 13.

    Montalbano M, Neff GW, Yamashiki N, Meyer D, Bettiol M, Slapak-Green G, et al. A retrospective review of liver transplant patients treated with sirolimus from a single center: an analysis of sirolimus-related complications. Transplantation. 2004;78:264–8.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Stallone G, Infante B, Grandaliano G, Gesualdo L. Management of side effects of sirolimus therapy. Transplantation. 2009;87(8S):S23–6.

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Xu SL, Zhang YC, Wang GY, Yang Q, Liu B, Zhang J, et al. Survival analysis of sirolimus-based immunosuppression in liver transplantation in patients with hepatocellular carcinoma. Clin Res Hepatol Gastroenterol. 2016;40:674–81.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Merin NM, Kelly KR. Clinical use of proteasome inhibitors in the treatment of multiple myeloma. Pharmaceuticals. 2016;8:1–20.

    Article  CAS  Google Scholar 

  17. 17.

    Richardson PG, Delforge M, Beksac M, Wen P, Jongen JL, Sezer O, et al. Management of treatment-emergent peripheral neuropathy in multiple myeloma. Leukemia. 2012;26:595–608.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Richardson PG, Briemberg H, Jagannath S, Wen PY, Barlogie B, Berenson J, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113–20.

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014;32:634–40.

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Humpel N, Iverson DC. Review and critique of the quality of exercise recommendations for cancer patients and survivors. Support Care Cancer. 2005;13:493–502.

    Article  PubMed  Google Scholar 

  21. 21.

    Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. New Engl J Med. 2015;372:426–35.

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Eghtedar A, Verstovsek S, Estrov Z, Burger J, Cortes J, Bivins C, et al. Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia. Blood. 2012;119:4614–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. 23.

    Harrison C, Mesa R, Ross D, Mead A, Keohane C, Gotlib J, et al. Practical management of patients with myelofibrosis receiving ruxolitinib. Expert Rev Hematol. 2013;6:511–23.

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Dahl K, Battisti JL. CNS demyelination during Anti TNF-alpha therapy (P4. 067). Neurology. 2015;84:P4–067.

    Google Scholar 

  25. 25.

    Rupasree Y, Naushad SM, Rajasekhar L, Uma A, Kutala VK. Association of TLR4 (D299G, T399I), TLR9− 1486 T > C, TIRAP S180L and TNF-α promoter (− 1031,− 863,− 857) polymorphisms with risk for systemic lupus erythematosus among South Indians. Lupus. 2015;24:50–7.

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Psarelis S, Hajineocli AP, Hadjicosta E, Elliott HS, Johnson P. Is secukinumab a safe alternative treatment for ankylosing spondylitis with Guillain Barré syndrome after anti-TNF-α treatment? Case report and literature review. Clin Rheumatol. 2017;36:1197–9.

    Article  PubMed  Google Scholar 

  27. 27.

    Kaltsonoudis E, Zikou AK, Voulgari PV, Konitsiotis S, Argyropoulou MI, Drosos AA. Neurological adverse events in patients receiving anti-TNF therapy: a prospective imaging and electrophysiological study. Arthritis Res Ther. 2014;16:R125.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 28.

    Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2012;31:88–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. 29.

    Sarcon A, Botta GP, Patel N, Saven A. Spontaneous iliopsoas muscle hemorrhage secondary to ibrutinib (Imbruvica; Pharmacyclics) brief report. J Invest Med High Impact case Rep. 2016;4:2324709616648457.

    Google Scholar 

Download references

Author contributions

JM, TA, and SKH wrote the first draft of the manuscript. All authors contributed substantially to the conception, acquisition, analysis, and interpretation of the data for the work.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jaleel Mohammed.

Ethics declarations

Conflicts of interest

There are no conflicts of interest to disclose from any authors.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mohammed, J., Akomolafe, T., Aljurf, M. et al. ‘To treat or not to treat’: raising awareness on the effects of graft versus host disease drugs on musculoskeletal system. Bone Marrow Transplant 53, 909–912 (2018). https://doi.org/10.1038/s41409-018-0095-7

Download citation

Further reading

Search