INTRODUCTION
Rheumatoid Arthritis (RA) is a systemic autoimmune disease that is characterized by inflammatory arthritis of the joints and extra-articular manifestations. According to the World Health Organization, the prevalence of RA varies between 0.3% and 1%. The disease is more commonly seen in women than in men.1 Though the etiology of RA is unclear, there is a clear indication of the interaction between genetics and environment. The heritability of RA varies significantly for seropositive (40%– 65%) and seronegative (20%) RA.
The current report presents the case of a 38-year old female with a family history of seropositive RA who showed secondary nonresponse to tumor necrosis factor inhibitor (TNFi) therapy. However, upon initiation of treatment with baricitinib, the patient demonstrated positive response with a reduced disease activity score (DAS) from 4.6 to 2.8 within a few months.
CASE PRESENTATION
A 38-year-old female patient, who was a known case of RA and on treatment with methotrexate, presented with severe pain and swelling in both the wrists, both hands, both ankles and both knees. She also complained of generalized weakness and morning stiffness in affected joints of more than 1.5 hours every day.
CLINICAL EXAMINATION
General Examination: Vitals: within normal range. BMI: 29. Local examination revealed the following findings
• Swelling and tenderness
» Bilateral wrist joints (more on the right)
» Right ring finger
» Bilateral ankle joints (more on the right side)
» Left knee joint
X ray of the hand (bilateral posteroanterior view) showed bilateral articular osteopenia without definite erosion in the wrists and metacarpophalyngeal joints.
INVESTIGATIONS
Table 1: Laboratory findings at diagnosis
ACPA: anti-citrullinated protein antibody; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein
Complete blood count, liver and kidney function tests were within normal range.
FAMILY HISTORY
Patient’s mother had RA (she died in 2013 while on treatment for carcinoma lung).
DRUG HISTORY
As reported by the patient, she was diagnosed with seropositive RA in June 2016 at a clinic in Egypt. She was on treatment with once weekly subcutaneous injection of methotrexate (15mg). She had on and off flaring up of the disease from 2016 to 2018, she reported taking over the counter non-steroidal antiinflammatory drugs to manage the pain.
MANAGEMENT
Biologic Treatment :

·          May 2018: After ruling out latent infections (tuberculosis, hepatitis B virus, hepatitis C virus), subcutaneous injection adalimumab (TNFi) was started (given once every 2 weeks). Oral methotrexate (20mg) was added with folate, vitamin D and calcium supplementation. Celecoxib (200mg) was given for pain relief. The DAS was reported to be 4.9

·           June 2018: Patient reported improvement of symptoms. DAS reduced to 4

·           August 2018: Response to treatment was good. DAS reduced to 3.9 and ESR was normal. However, the patient was not in remission

·           November 2018: Patient was overall happy with the treatment but reported on and off pain. She also complained of fatigue and quick exhaustion on performing physical activity. There was no swelling and DAS was 3.4

·           February 2019: Patient reported worsening of symptoms in this visit. She had stiffness in both the hands, pain in the knee joints. Biologic therapy was continued. The reported DAS was 4.6. She also expressed a desire to conceive but was advised against it as methotrexate is contraindicated in pregnancy

Targeted synthetic disease modifying anti-rheumatic drugs (tsDMARDs) :

·          May 2019: As there was no improvement in symptoms, patient was advised to stop biologic therapy and switch to oral baricitinib (4mg), a Janus kinase (JAK) inhibitor, once daily with oral methotrexate (15mg) weekly. After 2 weeks on treatment, patient reported improvement in symptoms and decrease in morning stiffness. However, more time was needed to evaluate the benefit of the therapy and to keep a close watch on adverse effects, if any

·           June 2019: Patient reported significant improvement in pain and other symptoms. She was able to perform physical activities with much more ease than earlier

MANAGEMENT (CONTD.)
Targeted synthetic disease modifying anti-rheumatic drugs (tsDMARDs)

·          October 2019: The reported DAS reduced to 2.9 and the ESR was normal

·           March 2020: ESR and CRP remained in normal range. Patient reported improvement in her daily life and overall quality of life. Weekly telephonic follow ups were continued (pertaining to coronavirus travel restrictions). Patient was advised to follow extreme caution to avoid infection

·           September 2020: Patient achieved both clinical and lab remission. DAS was 2.8. ESR was 24 mm/hr and CRP was 3.9 mg/dl. The dose of methotrexate was tapered down to 7.5mg and gradually discontinued in October 2020

The outline of the clinical and laboratory findings of this patient at different visits throughout the course of her treatment is presented in Table 2.
Table 2: Clinical and laboratory finding during follow-ups
OUTCOME
Patient has achieved remission with baricitinib without any adverse effects.
DISCUSSION
Disease modifying anti-rheumatic drugs (DMARDs) are the mainstay of treatment in RA. They act by modifying the immune response of the body by interfering with critical pathways in the inflammatory cascade and thereby reducing inflammation. There is no one size fits all treatment for RA patients. Response to treatment can vary from one patient to another based on the individual. It is not uncommon for a patient to develop resistance or intolerance to a DMARD. Treating rheumatologists need to adjust the type of drug and dose until a satisfactory response is achieved.
A real-world observational study of patients in the United States revealed that switching to a new DMARD with a different mechanism of action after loss of response to one TNFi, was associated with significantly better treatment persistence as compared to TNFi cycling.3 Similarly, in this case switching from TNFi to baricitinib, a tsDMARD, proved beneficial. Initially, this patient showed response to treatment with a TNFi for almost a year. Her clinical symptoms as well as laboratory findings suggested a move to remission until she had a flare up and stopped responding. After starting baricitinib, patient has sustained remission for more than a year and has been closely monitored for any potential adverse effects. This case substantiates the effectiveness of baricitinib in treating patients with secondary resistance to adalimumab.
DISCUSSION (CONTD.)
Another notable feature of this case is the concern of the patient to conceive. Methotrexate is contraindicated and for other DMARDs the data is insufficient.4,5 Hence, DMARDs may not be ideally recommended during pregnancy. In patients who desire to conceive, rheumatologists must discuss the risks and benefits of antirheumatic therapy during conception, pregnancy and lactation. Better maternal and fetal outcomes can be expected if the pregnancy is planned after low disease activity has been achieved or when the medication is gradually tapered or discontinued.
Lessons Learnt:
• Regular follow up is extremely important when treating RA to monitor treatment response and side effects. Treating rheumatologist should assess the patient’s response to treatment and switch drugs accordingly
• In women of childbearing age and on RA treatment, discussing a safe time for conception is critical
• Baricitinib proved to be effective in a patient who was a secondary non-responder to biologic therapy
REFERENCES

1 WHO. Chronic rheumatic conditions. https://www.who.int/chp/topics/rheumatic/en/.

  Accessed 25 November 2020; 2Chauhan K, Jandu JS, Goyal A, Bansal P, Al-Dhahir MA. Rheumatoid Arthritis. In: StatPearls. Treasure Island (FL)2020; 3Wei W, Knapp K, Wang L, et al. Treatment Persistence and Clinical Outcomes of Tumor Necrosis Factor Inhibitor Cycling or Switching to a New Mechanism of Action Therapy: Real-world Observational Study of Rheumatoid Arthritis Patients in the United States with Prior Tumor Necrosis Factor Inhibitor Therapy. Adv Ther. 2017;34(8):1936-1952; 4Ngian GS, Briggs AM, Ackerman IN, Van Doornum S. Safety of anti-rheumatic drugs for rheumatoid arthritis in pregnancy and lactation. Int J Rheum Dis. 2016;19(9):834-843; 5Temprano KK, Bandlamudi R, Moore TL. Antirheumatic drugs in pregnancy and lactation. Semin Arthritis Rheum. 2005;35(2):112-121

Categories: Rheumatology

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