A 34-year-old female with 10 years history of rheumatoid arthritis, frequent episodes of fever, and weight loss

This 34-year-old patient managed with a triple-drug combination of DMARDs - methotrexate, leflunomide, and hydroxychloroquine - presented with recurrent fever and weight loss. She did not have any localizing symptoms, RA was well controlled, and inflammatory parameters and liver enzymes were normal. Under the circumstances, the possibilities one must suspect are drug-induced fever, metabolic causes of fever such as hyperthyroidism, development of infections like tuberculosis and other opportunistic infections, malignancy, and development of systemic features of RA. Although such cases are seen less often, this kind of clinical situation is not uncommon.

In the presence of infection, there can be low localizing signs due to the use of Immunosuppressive drugs. There is increased susceptibility to tuberculosis with leflunomide as well as methotrexate, with the risk being higher with the former.^1,2 Screening for tuberculosis (TB) including chest radiograph and abdominal scanning will assist in identifying any site of TB. The patient's chest X-ray and Monteux test were negative. Normal ESR and CRP suggested a lesser possibility of TB. Auto-immune thyroid disease can also co-occur along with RA. Typical weight loss and normal appetite suggest the possibility of hyperthyroidism where the patient may have elevated temperature. A screening test for thyroid dysfunction could address this possibility. However, the thyroid function test was also found to be normal in the current patient.

Screening for malignancy is recommended although the patient is young. The incidence of malignancy is known to be moderately increased in patients with RA.³ The commonly expected malignancies include lymphoproliferative malignancy and pulmonary and colorectal malignancies. The persisting normal blood count and ESR suggested that lymph-proliferative malignancy is less likely. Occult blood in stool, if clinically indicated, also indicates malignancy. However, these tests were negative in this patient.

Serum ferritin levels are usually elevated in the presence of development of the systemic feature.⁴ However, serum was normal for the present patient. Given this, the fever was considered a drug-induced fever in all probability, and secondary to leflunomide. Weight loss can also be attributed to the same drug, as it was known to be an observable adverse event of leflunomide.^5-7 A clinical trial by Coblyn et al. has reported that 5 out of 70 patients screened had significant weight loss.⁸ This is often overlooked in normal clinical practice and should be considered to avoid extensive investigation. With most screening tests being negative, the final diagnosis is Leflunomide-induced fever and weight loss. The patient was advised to discontinue leflunomide, following which fever subsided by the end of four weeks and she gained weight over the next two months. Fever was not disabling, and washout was not contemplated.

Final Diagnosis

RA with drug (leflunomide) induced fever and weight loss

Lesson to learn

A careful follow-up for the development of new symptoms is required. Possible drug reactions like fever and weight loss should be considered. A minimum screening to exclude other possibilities helps to consider potentially treatable conditions.

References

1. Schiff MH, Strand V, Oed C, Loew-Friedrich I. Leflunomide: efficacy and safety in clinical trials for the treatment of rheumatoid arthritis. Drugs of today2000;36(6):383-394.
2. Kalden JR, Schattenkirchner M, Sorensen H, Emery P, Deighton C, Rozman B, et al. The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year follow-up study. Arthritis and rheumatism2003;48(6):1513-1520.
3. Smitten AL, Simon TA, Hochberg MC, Suissa S. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res and Therapy2008;10(2):R45.
4. Rosario C, Zandman-Goddard G, Meyron-Holtz EG, D'Cruz DP, Shoenfeld Y. The hyperferritinemic syndrome: macrophage activation syndrome, Still's disease, septic shock and catastrophic antiphospholipid syndrome. BMC Medicine2013;11:185.
5. Mladenovic V, Domljan Z, Rozman B, Jajic I, Mihajlovic D, Dordevic J, et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Results of a randomized, placebo-controlled, phase II study. Arthritis and rheumatism1995;38(11):1595-1603.
6. Smolen JS, Kalden JR, Scott DL, Rozman B, Kvien TK, Larsen A, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet1999;353(9149):259-266.
7. Rozman B. Clinical experience with leflunomide in rheumatoid arthritis. Leflunomide Investigators' Group. J RheumatolSupplement 1998;53:27-32.
8. Coblyn JS, Shadick N, Helfgott S. Leflunomide-associated weight loss in rheumatoid arthritis. Arthritis and Rheumatism2001;44(5):1048-1051.