Recommendations of the Brazilian Society of Rheumatology for the diagnosis and treatment of chikungunya fever. Part 2 - Treatment

Marques, Claudia Diniz Lopes; Duarte, Angela Luzia Branco Pinto; Ranzolin, Aline; Dantas, Andrea Tavares; Cavalcanti, Nara Gualberto; Gonçalves, Rafaela Silva Guimarães; Rocha, Laurindo Ferreira da; Valadares, Lilian David de Azevedo; Melo, Ana Karla Guedes de; Freire, Eutilia Andrade Medeiros; Teixeira, Roberto; Neto, Francisco Alves Bezerra; Medeiros, Marta Maria das Chagas; Carvalho, Jozélio Freire de; Santos, Mario Sergio F.; Océa, Regina Adalva de L. Couto; Levy, Roger A.; Andrade, Carlos Augusto Ferreira de; Pinheiro, Geraldo da Rocha Castelar; Abreu, Mirhelen Mendes; Verztman, José Fernando; Merenlender, Selma; Ribeiro, Sandra Lucia Euzebio; Costa, Izaias Pereira da; Pileggi, Gecilmara; Trevisani, Virginia Fernandes Moça; Lopes, Max Igor Banks; Brito, Carlos; Figueiredo, Eduardo; Queiroga, Fabio; Feitosa, Tiago; Tenório, Angélica da Silva; Siqueira, Gisela Rocha de; Paiva, Renata; Vasconcelos, José Tupinambá Sousa; Christopoulos, Georges

doi:10.1016/j.rbre.2017.06.004

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Original articles • Rev. Bras. Reumatol. 57 (suppl 2) • 2017 • https://doi.org/10.1016/j.rbre.2017.06.004 copy

Recommendations of the Brazilian Society of Rheumatology for the diagnosis and treatment of chikungunya fever. Part 2 - Treatment

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Chikungunya fever has become an important public health problem in countries where epidemics occur because half of the cases progress to chronic, persistent and debilitating arthritis. Literature data on specific therapies at the various phases of arthropathy caused by chikungunya virus (CHIKV) infection are limited, lacking quality randomized trials assessing the efficacies of different therapies. There are a few studies on the treatment of musculoskeletal manifestations of chikungunya fever, but these studies have important methodological limitations. The data currently available preclude conclusions favorable or contrary to specific therapies, or an adequate comparison between the different drugs used.

The objective of this study was to develop recommendations for the treatment of chikungunya fever in Brazil. A literature review was performed via evidence-based selection of articles in the databases Medline, SciELO, PubMed and Embase and conference proceedings abstracts, in addition to expert opinions to support decision-making in defining recommendations. The Delphi method was used to define the degrees of agreement in 2 face-to-face meetings and several online voting rounds. This study is part 2 of the Recommendations of the Brazilian Society of Rheumatology (Sociedade Brasileira de Reumatologia - SBR) for the Diagnosis and Treatment of chikungunya fever and specifically addresses treatment.

Keywords:
Chikungunya fever; Treatment; Consensus; Brazil

C. Treatment
C.1. In the acute phase of chikungunya fever, common analgesics and/or weak opioids should be used (in cases of severe or refractory pain), and NSAIDs and salicylates should be avoided. Corticosteroids (CSs) are not recommended for musculoskeletal manifestations in this phase. Agreement: 9.31 (SD ± 0.8906). GRADE: very low quality of evidence.
C.2. In the subacute phase of chikungunya fever, NSAIDs and/or adjuvant drugs may be used for pain management (anticonvulsants or antidepressants) in cases refractory to analgesics/opioids. In patients with moderate to severe musculoskeletal pain or in those with contraindications to the use of these drugs, the use of prednisone or prednisolone at a dose of up to 20 mg/day is recommended, and withdrawal should be performed slowly and gradually, according to patient response. Agreement: 9.24 (SD ± 1.057). GRADE: low to very low quality of evidence.
C.3. In the chronic phase of chikungunya fever, the use of analgesics is recommended for symptom relief. Weak opioids (codeine and tramadol) may be used for refractory or severe pain symptoms (VAS ≥7). Agreement: 9.57 (SD ± 0.741). GRADE: low to very low quality of evidence.
C.4. In the chronic phase of chikungunya fever, NSAIDs are recommended, taking into consideration the clinical context, contraindications and therapeutic response. Agreement: 8.97 (SD ± 1.679). GRADE: low to very low quality of evidence.
C.5. In the chronic phase of chikungunya fever, oral corticosteroids may be used for musculoskeletal and neuropathic complaints, and low doses are recommended (5-20 mg/day prednisone or prednisolone). The time of use may range from six to eight weeks, and withdrawal should be slow and gradual due to the risk of recurrence of joint symptoms. Agreement: 9.24 (SD ± 1.154). GRADE: low to very low quality of evidence.
C.6. In the chronic phase of chikungunya fever, antimalarials, preferably hydroxychloroquine, may be used for the treatment of joint symptoms, alone or in combination with MTX or SSZ. Agreement: 9.21 (SD ± 1.166). GRADE: low quality of evidence.
C.7. In patients with chikungunya fever progressing to the chronic phase and with inflammatory joint disease, with difficulties in CS withdrawal, we preferentially suggest MTX at doses of 10-25 mg/week. Agreement: 9.43 (SD ± 0.858). GRADE: low to very low quality of evidence.
C.8. In the chronic phase of chikungunya fever, sulfasalazine may be used at a dose of 2 to 3 g/day, alone or in combination, especially in patients with contraindication to or failure with MTX. Agreement: 8.77 (SD ± 1.794). GRADE: low to very low quality of evidence.
C.9. Biological therapy may be prescribed after rheumatologist evaluation of patients with chronic inflammatory joint disease after infection with CHIKV, refractory to the use of CS and DMARDs, following the recommendations used to treat RA or SpA. Agreement: 8.97 (SD ± 1.267). GRADE: low to very low quality of evidence.
C.10. During the acute phase, in patients undergoing biological therapy for their underlying disease, drug therapy discontinuation is recommended. However, treatment can be maintained in the subacute and chronic phases. Agreement: 8.97 (SD ± 1.884). GRADE: low to very low quality of evidence.
C.11. Rehabilitation interventions in all phases of chikungunya fever are recommended as a complementary non-pharmacological measure. In the acute phase, analgesic and anti-inflammatory therapies are indicated, and the use of heat should be avoided; furthermore, patient education, posture guidelines and manual therapy should be recommended, in addition to light-intensity exercise. In the subacute and chronic phases, the previous recommendations should be followed, which may also include heat, in addition to free, resisted, proprioceptive and active aerobic exercises, stretching, manual therapy and aquatic physical therapy. Agreement: 9.43 (SD ± 0.935). GRADE: very low quality of evidence.

Drug	Dose	Monitoring and precautions
Paracetamol	60 mg/kg/day, without exceeding 4 g/day, orally, 4 times a day	The increased risk of hepatitis resulting from the association of viremia, drug interactions and comorbidities (liver or kidney disease or alcoholism) with high doses of paracetamol should be carefully monitored.
Dipyrone	1 g, orally, 4 times a day	Evaluate kidney and liver function, especially in the elderly.
Tramadol	50 mg to 100 mg, orally, 2-4 times a day	In patients over 65 years of age, start with the lowest dose; in patients older than 75 years, do not exceed 300 mg/day. Risk of respiratory depression in the elderly.
Paracetamol + Codeine	500 mg + 30 mg, orally, 2-4 times a day	Evaluate hepatotoxicity.
NSAIDs	Depending on the compound chosen	Use the lowest dose for the shortest possible time. Never use two NSAIDs in combination. Evaluate the risk factors: age >65 years, previous history of ulcer, SAH, kidney disease, use of CS, anticoagulants, asthma and smoking. Monitor blood pressure, peripheral edema and kidney function.
Amitriptyline	25-50 mg/day, orally	Use with caution in patients with cardiovascular disease, diabetes mellitus, mania, kidney or liver failure, thyroid dysfunction or epilepsy. Withdrawal should be gradual.
Gabapentin	300 mg, 2-3 times a day, orally	In children aged 3-12 years, there is a risk of neuropsychiatric adverse events (emotional lability, hostility, thought disorders and hyperkinesia). Withdrawal should be in phases.
Pregabalin	50-150 mg, 2-4 times a day, orally	Use with caution in patients with heart and kidney failure. Monitor thrombocytopenia and symptoms of dependence. Withdrawal should be gradual.
Prednisone/Prednisolone	5-20 mg/day, preferably a single dose in the morning Higher doses may be used in severe cases	Assess the presence of risk factors for osteoporosis, glaucoma (family history) and diabetes mellitus. Monitor blood pressure and fasting blood glucose.
Antimalarials	5.0 mg/kg HCQ and 3 mg/kg chloroquine, orally, 1 time a day	With risk factors for retinal toxicity^a a Dose >5 mg/kg/day; treatment length; previous ocular disease; kidney disease; liver disease; use of tamoxifen; advanced age (risk of age-related ocular diseases complicating toxicity assessment). : previous ophthalmologic evaluation; annual re-evaluation. Without risk factors: there is no need for prior evaluation; re-evaluation after 5 years of treatment.
Methotrexate	10-25 mg/week, orally or SC	Hemogram, transaminases, and kidney function prior to initiation of treatment and every 3 months. Potentially teratogenic. The use of folic acid (5 mg, orally, weekly, the day after MTX) reduces the risk of adverse events. Risk of pulmonary toxicity.
Sulfasalazine	1-2 g/day, orally	Hemogram, transaminases and kidney function prior to initiation of treatment and every three months. May cause orange urine or skin.
Anti-TNFs	Infliximab, Etanercept, Adalimumab, Golimumab, Certolizumab	Screening - the same recommendations as the current protocols for RA and SpA. Respiratory symptoms must be carefully monitored - risk of reactivation of latent tuberculosis.

Objectives	Acute phase	Subacute and chronic phases
Pain and swelling reduction	Cryotherapy TENS Manual therapy Compression bandages	Electrothermal therapy and phototherapy (ultrasound, low-power laser) Manual therapy Aquatic physical therapy
Maintenance of joint function	Light, active exercise (caution) Orthoses	Manual therapy Therapeutic exercises: passive and free and resisted active exercises - progressive Stretching Proprioceptive training Aquatic physical therapy
Physical fitness improvement		Aerobic exercise
Posture	Avoid painful postures Adoption of decubitus positions favoring venous return	Stretching
Avoid	Use of heat - may worsen the inflammatory response	Prolonged joint immobilization
Patient education	Advice about the disease Strategies supporting treatment Adjustment of environmental and individual factors that may affect the course of the disease

Sociedade Brasileira de Reumatologia Av Brigadeiro Luiz Antonio, 2466 - Cj 93., 01402-000 São Paulo - SP, Tel./Fax: 55 11 3289 7165 - São Paulo - SP - Brazil
E-mail: sbre@terra.com.br

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[1] *Corresponding author. E-mail: claudia.reumatologia@gmail.com (C.D. Marques).