Atypical Neurological and Gastrointestinal of Undifferentiated Systemic Rheumatic Disease/Overlap Syndrome Responded to JAK2 Inhibitor

Mehrdad Ayati^1* and Arezou Azarani^2
*Correspondence: Mehrdad Ayati, Department of Med/Primary Care and Population Health, Stanford University School of Medicine, Stanford Hospital, CA 94305, California, USA, Tel: +650-808-0180, Email:

Keywords

PPPD • Undifferentiated systemic rheumatic disease • Neurological disease • Dizziness • Vestibular migraine • Fibromyalgia • Behcet's disease • TNF alpha • JAK 2 Inhibitor • Overlap syndrome

Introduction

A female patient suffered from an early age from nausea, migraines, GI upsets, joint pains, dactylitis, eye irritations, oral and vaginal ulcers, morning stiffness, Raynaud, on and off low grade fever, dysmenorrhea, pelvic and lower back pain, vaginal burning, GERD, IBD (Inflammatory Bowel Disease), and IC. As she got older her symptoms worsened, and in addition she suffered from acute vertigo and dizziness, hearing loss, fibromyalgia, dermatological issues, seizures, hypertension and tachycardia, Hashimoto thyroiditis, anxiety, as well as kidney disease. All of her medical manifestations were addressed, organ by organ, by different specialists, and at different stages of her life. Whether all these complex medical issues could have a common underlying casue, however, was never considered.

Case Presentation

Juvenile arthritis

In her early teens, the patient became symptomatic in her large joints. She suffered from swelling and pain in her Acromio Clavicular (AC) and knee joints bilaterally, and was diagnosed with seronegative JRA [1]. She received multiple steroid intraarticular injections. These injections alleviated her symptoms temporarily. In addition, she started experiencing various extraarticular symptoms.

GI involvement

In her late teens, the patient was diagnosed with UC [2] after episodes of lower gastrointestinal bleeding, confirmed with colonoscopy and biopsy. The area of involvement was up to 60 cm of the left colon. Multiple biopsies ruled out the presence of the Crohn's disease. She was treated with 5- Amino Salicylic Acid (5-ASA), 200 mg three times a day, and steroid rectal enema for flare-ups [3]. Episodes of rectal bleeding continued into her late 20s. In her late 30s, multiple routine follow-up colonoscopies were consistent with no ulceration and she was advised to stop her 5-ASA. Since then, her colonoscopies only revealed patchy areas of colitis (confirmed with biopsies) in the left colon area but no ulceration.

In addition, she has been suffering from severe GERD, confirmed with 24 hours PH assays and multiple Esophago gastro duodenoscopies, complicated with Peptic Ulcer Disease. Many biopsies of the stomach and esophagus denied the presence of the Helicobacter Pylori infection. As a result, the patient has been treated with different types of Proton Pump Inhibitors (PPIs) at the maximum dose, including Lansoprazole, Dexlansoprazole and Esomeprazole.

Furthermore, over the years, the patient developed significant intolerances, allergies and maldigestions toward many food products (such as fibers, gluten, dairy and soy protein) as well as allergies toward medications (Table 1).

She continuously suffered from bloating, nausea, and epigastric pain. She underwent many digestive health studies that ruled out conditions such as gastric motility disorders and Small Intestine Bacterial Overgrowth Syndrome. The patient was also negative for celiac disease. She was empirically treated with multiple courses of Xifaxan antibiotic to no effect. High doses of different kinds of probiotics were ineffective. It was also recommended that the patient follows many types of food diets such as FODMAP diet, but the patient did not experience any improvements from her GI symptoms. As such, the patient's diet for many years was limited to rice, potato, and meat. Other symptomatic interventions, including Gabapentin or Tri Cyclic Antidepressants (TCAs), did not help the patient’s GI symptoms and carried significant side effects.

Urogenital involvement

Since puberty, the patient suffered from severe dysmenorrhea, pelvic and lower back pain, and vaginal burning. In her 20s, she was diagnosed with extensive Endometriosis [4]. She was treated with oral Estrogen-Progestin and Gonadotropin Releasing Hormone (GnRH) analogs (Leuprolide) with no improvement and extensive side effects. She underwent multiple excision and ablation of endometriotic lesions and in her mid-30s, a TVH/BSO. She was not placed on Hormone Replacement Therapy after TVH/BSO due to possible risk of relapse.

Concurrently, the patient developed severe symptomatic IC [5], manifested by persistent Bladder Pain Syndrome. She did not respond to numerous interventions including pharmacological therapies such as Amitriptyline, Pentosan polysulfate sodium, antihistamines and Gabapentine. Multiple Bladder hydrodistension with intravesical therapies to target the Hunner lesions with local anesthetics (such as Lidocaine, Bupivacaine, Capsaicin) Glycosaminoglycans (both heparin and hyaluronic acid), sodium bicarbonate and Dimethylsulfoxide were ineffective [6-8]. The patient also underwent years of pelvic floor physical therapy and was advised to consume a diet low in oxalate [9]. However, none of the above recommendations gave the patient any relief from IC.

Mucocutaneous lesions

Since the onset of the patient’s polyarthritis she has had significant episodes of painful oral and vaginal lesions. The oral lesions were aphthous ulcerations in nature (canker sores), multiple and extensive, ranging from a few millimeters to 1 cm. The healing course for the oral ulcers with surrounding erythema ranged between 2-4 weeks. Treatment with topical Triamcinolone paste has been very effective for her oral ulcers. The urogenital lesions, very similar to her oral aphthae, did not respond to any topical treatments including Colchicine.

During the course of her disease, the patient has developed large areas of patchy distribution and hyperpigmented lesions associated with severe pruritus (Figure 1). It has been treated empirically with topical high-potency steroids, intra-lesional steroid injections, and topical anti-fungal medications to no effect. Her biopsy was consistent with localized cutaneous amyloidosis [10].

Neurological involvement

Starting in her late 30s, along with other musculoskeletal and GI symptoms, the patient started experiencing multiple episodes of sudden vertigo, periodic dizziness, dysequilibrium, severe neuropathic symptoms with tingling and burning sensations in lower extremities, sleep impairment with insomnia, and multiple episodes of Hypnic jerks and Restless Legs Syndrome [11]. Her neurological symptoms worsened over time and became persistent dysequilibrium and dizziness, impairing her balance and mobility.

Due to her persistent dizziness and vertigo, the patient underwent extensive ENT assessments. Peripheral vestibulopathy was ruled out. She was diagnosed with Vestibular Migraine and/or PPPD [12]. Empirical use of antihistamines, systemic steroids, Selective Serotonin Reuptake Inhibitors, Serotonin and Norepinephrine Reuptake Inhibitors, Gamma-Aminobutyric Acid analogs, and Benzodiazepines proved ineffective with numerous side effects. Long term cognitive behavioural therapy and extensive Vestibular Therapy were also ineffective.

Multiple CT-Scans and MRIs of patient’s brain and ears were normal except for extensive opacification of the left-sided mastoid air cells. The ENT and Neurology teams could not determine the cause, nor did they diagnose it as chronic mastoiditis. No specific treatment was recommended for this issue. It was also determined that, over a period of a year, the patient had lost 30% of her left ear hearing.

Thyroid disease

In her early 50s, the extent of the patient's Rheumatological and Neurological symptoms amplified. She experienced generalized fatigue, hair loss, brittle nails, increased sensitivity to cold and hot temperatures, dry skin, heart palpitations, labile hypo, and hypertension. In endocrinological evaluation, all tests for Pheochromocytoma, including 24 hours urine fractionated metanephrines and catecholamines, were normal. Her TSH fluctuated between normal range to subclinical hypothyroidism level, but her Anti-TPO was constantly on the high side (Table 2).

She was diagnosed with Hashimoto thyroiditis [13]. The ultrasound of the thyroid gland was normal. The patient was put on a low-dose of synthetic thyroxine T4 therapy. However, thyroxine therapy did not resolve her medical symptoms and also caused her severe palpitation and labile hypertension and had to be stopped.

Chronic kidney disease

In her 50s, with the peak of neurological, rheumatological and GI manifestations, the patient’s Glomerular Filtration Rate (GFR) started to decline from normal to Chronic Kidney Disease (CKD) stage 3 level [14] (Table 3). Her kidney’s ultrasound was consistent with a bilateral increase in echogenicity. The cause of her Interstitial Nephritis was hypothesized to be due to immunological or pharmacological reasons. The patient had consumed many years of proton pump inhibitors to manage her GERD and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) to manage her extensive pains.

Rheumatological manifestations

As discussed above, the patient’s rheumatological symptoms initially started with seronegative JRA in her teens. Throughout her life, she experienced asymmetric migratory joint pain and effusion in large joints, distal interphalangeal joints, thumb bases, proximal interphalangeal joints, and second and third metacarpophalangeal joints. On a daily basis, the patient experienced more than 30 minutes of morning stiffness. At the same time, she had symptoms of axial Spondyloarthritis (axSpA) with pain in Sacroiliac joints and spine area with limited range of motion of the lower spine area, enthesitis and dactylitis. Additionally, the patient had been suffering from severe Raynaud phenomenon [15] and fibromyalgia [16] since her teen years. These symptoms magnified in her late 40s. Multiple Rheumatologists evaluated her. Table 4 indicates the patient’s inflammatory markers and Table 5 indicates the patient’s immunological markers.

The first Rheumatologist impression was that the patient suffered from Systemic Lupus Erythematosus (SLE) [17] due to an elevated AntiNuclear Antibodies (ANA) (320 with IF) (Table 5). However, the rest of her tests were normal. She was prescribed Hydroxychloroquine, which she could not tolerate due to severe side effects. Later she was put on systemic oral steroids, but they were also stopped due to severe GI side effects, worsening headaches and dizziness.

In her early 50s, the patient was extremely sick. She could no longer work. She lost a lot of weight (over 10kg from 58kg to 48kg), could not perform her routine functions, and was in agonizing pain. Therefore, another Rheumatologist was consulted. The second Rheumatologist did not agree with the diagnosis of SLE. It was suggested that the patient suffered from a subtype of Spondyloarthropathy (SpA) [18], or IBD arthropathy (given her history of UC and significant GI disturbances) [19-22], or Undifferentiated Systemic Rheumatic Disease (USRD) [23], or the Overlap Syndrome [24]. Consequently, she was put on a Tumor Necrosis Factor (TNF) alpha inhibitor therapy [25- 27], Adalimumab (Humira, 40 mg every two weeks). TNF alpha inhibitors are human monoclonal antibodies (thus called biologic disease modifying agents). The patient responded relatively well after the second dose of Adalimumab and reported a 50% reduction in her rheumatological symptoms, vertigo, dizziness and neuropathy. However, Adalimumab provided only minimal improvement in her GI disturbances. During TNF alpha therapy, the patient still had flare-ups of her joints pain and was put on and off on Prednisone therapy.

After six months of treatment, the effect of Adalimumab got lessened, and her dose was increased to a weekly basis and even a higher dose to no effect. After multiple consultations with different Rheumatologists it was determined that the patient had developed antibody against Adalimumab [28,29]. Their suggestion was switching her to a different type of TNF alpha inhibitor or starting a new agent such as JAK2 inhibitor therapy [30,31]. To prevent further antibody development against a biologic agent the decision was to start the patient on a JAK2 inhibitor therapy called upadacitinib (Rinvoq at 15 mg/day). Probable diagnosis was non-radiological axial spondyloarthritis vs. IBD arthropathy.

After taking Rinvoq for three months, the patient reported having a reduction of approximately 60% in her symptoms, including vertigo, dizziness, joint and muscle pains, headaches, fatigue, IC, GI pain, acid reflux, numbness and tickling in her extremities, neuropathy, mouth and genital ulcers, inflamed eyes, and tinnitus. After six months, the patient reported a decrease of approximately 80% in her symptoms. After years of being unable to eat due to severe GI pains, the patient started eating a normal diet, including fibers and many of the foods she used to be intolerant to. After years of weight loss, she started gaining weight (over 10 kg). She also reported having fewer flareups and much better sleep patterns after years of insomnia. She experienced fewer Hypnic jerks. After a year of being on Rinvoq, the patient reported a reduction of 95% of her symptoms. Her kidney function and TPO Antibody level both improved significantly after the treatment (Tables 2 and 3). And she no longer needed Prednisone therapy in conjunction with JAK2 inhibitor to address relapses.

Results and Discussion

The complexity of this patient’s diagnosis lies in the fact that she suffered from numerous, highly intricated medical conditions involving multi organs. And by the fact that all of her medical manifestations were address organ by organ by different specialists. For example, her UC was address at an early age with 5-ASA. Derivatives of 5-ASA are anti-inflammatory drugs that help to reduce symptoms of ulcerative colitis by blocking the activity of cyclooxygenase and lipoxygenase, thereby reducing the production of prostaglandins [2,3]. But, at the same time, she was suffering from seronegative JRA, GERD, IBD, endometriosis, IC, Raynaud, localized cutaneous amyloidosis and fibromyalgia. Each of these clinical expressions, in her different body parts, was address separately either by pharmacological means or surgical interventions. However, the patient would have benefited immensely if all of these symptoms were considered to have a shared underlying cause.

As the research in the area of immunological disorders expands, it is more and more clear that many of such conditions have an underlying rheumatological origin. As an example, SpAs [18] are a family of joint disorders, which include IBD associated arthritis (or IBD arthropaty) [19-22], Psoriatic Arthritis (PsA), Ankylosing Spondylitis (AS), reactive arthritis, and undifferentiated SpA. Patients with SpA often present with inflammatory joint pain characterized by morning stiffness lasting more than one hour and improving with activity [18].

The most common extraintestinal manifestation of IBD is arthritis. Arthropathy associated with IBD is a type of SpA with axial and/or peripheral joint manifestations and a negative rheumatoid factor [20]. The peripheral arthritis is mostly non-erosive and may correlate with intestinal disease activity. Axial arthritis can include ankylosing spondylitis, inflammatory back pain, or sacroiliitis and does not always correlate with gastrointestinal symptoms.

The link between gut and joint inflammation in IBD is currently unknown. However, two major theories explain the development of arthritis in IBD patients. First is the presence of gut bacteria and the second is the migration of gut lymphocytes to the joints [20].

While the specific causes of most types of SpAs are unknown, people who have a gene known as HLA-B27 are at a higher risk of developing AS, IBD associated arthritis, PsA, and reactive arthritis. However, not everyone expressing this gene will develop the disease. The patien in this study did not carry the HLA-B27 gene. Several non-HLA genes have also been identified in SpAs pathogenesis. Males have a higher risk of developing SpAs compared to females. In addition to genetic factors, environmental factors such as bacterial infections, stress, and microtrauma can also increase the risk of SpAs.

Several cytokines have been shown to participate in the inflammatory process of the SpAs. One of these cytokines is TNF alpha. Macrophages and macrophage-driven cytokines such as TNF-alpha and IL10 are mediators of disease inflammation. A few anti-TNF alpha therapies (infliximab, etanercept, adalimumab, golimumab, and certolizumab) have resulted in partial or full remission of symptoms in many patients. Treatment with TNF alpha inhibitors (human monoclonal antibodies also called biologics) has been recommended for patients suffering from IBD arthropathy. However, many patients treated with TNF alpha inhibitors, can over time, develop antibodies against them and make their action ineffective [28,29].

That is in fact what happened to this patient after six months of therapy with TNF alpha inhibitor Adalimumab. As such, the patient was treated with JAK2 inhibitor [30]. Janus kinase family of enzymes include JAK1, JAK2, JAK3, and TYK2. They are cytoplasmic tyrosine kinases associated with membrane cytokine receptors that mediate signaling of multiple cytokines and growth factors, contributing to the pathogenesis of multiple autoimmune disorders [31]. Therefore, JAK inhibitors are immune modulating medications, which inhibit the activity of one or more of the Janus kinase family of enzymes by interfering with the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) signaling pathway in the lymphocytes [31]. They are used in the treatment of inflammatory diseases, rheumatoid arthritis, cancer and multiple skin conditions such as psoriatic arthritis. Patients treated with JAK inhibitors (called synthetic disease modifying drugs) do not develop antibodies against them as they are not monoclonal antibodies. They are targeted therapies, which act at a molecular level.

Partial response of the patient to TNF-alpha and almost full response to JAK2 inhibitor therapies is a strong indication that many of her clinical manifestations have an underlying immunological origin. The patient has widespread inflammation with systemic features that overlap specific rheumatic diseases. However, her exact rheumatic disease can’t be definitively classified. Over a quarter of patients suffering from rheumatic disease having systemic symptoms can’t be easily diagnosed. Diagnosing and treating rheumatic diseases is one of the biggest challenges for many providers, including primary care physicians and specialists. Many patients can never be appropriately diagnosed, even years after the disease becomes symptomatic.

Here, a few theoretical immunological diagnoses for this patient are presented. The first theory is that this patient could be suffering from IBD arthropathy, which is a subtype of seronegative SpA. This theory is based on her history of UC, and many rheumatological symptoms such as joint disease.

Another theory is that this patient could be suffering from an USRD [23] or an Overlapped Syndrome [24]. If patients have features characteristic of an autoimmune disease such as Raynaud’s phenomenon, arthralgias, myalgias or a positive ANA but do not meet criteria for a defined autoimmune disease they can be diagnosed as USRD. Other patients who meet criteria for two or more defined autoimmune conditions can be diagnosed by overlap syndrome. These patients suffer from an immunological disorder that overlaps many of the known auto inflammatory disorders such as Lupus, rheumatoid arthritis, mixed connective tissue disease, Behcet’s Disease (BD), IBD arthropathy or seronegative SpA.

The patient in this case had early Raynaud phenomena. Her polyarthritis was presented with diffuse or migratory arthralgia, symmetrical or asymmetrical polyarthritis or oligoarthritis, migratory polyarthritis, prolonged morning stiffness, elevated erythrocyte sedimentation rate, positive ANA, and a dramatic response to anti-inflammatory therapy. Although this pattern suggests Rheumatoid Arthritis (RA), it does not fulfil the current criteria for diagnosing RA and it could be classified under USRD or overlap Syndrome.

Another possible classification of this patient’s diagnosis could be under a subset of BD [32]. BD is a relatively uncommon chronic auto inflammatory disorder seen in patients of Eastern Asia to the Mediterranean (the ancient Silk Road) descent. It is a relapsing; multisystemic/multiorgan disorder characterized by mucocutaneous, ocular, vascular and central nervous system manifestations. Its clinical spectrum includes oral and genital ulcerations, uveitis, vascular, neurological, articular, renal and gastrointestinal manifestations. While the etiopathogenesis of the disease is unknown, genetic predisposition, environmental factors and immunological abnormalities have been implicated [32-34].

While HLA-B51 and HLA-B5 are important genetic factors in determining BD in clinical phenotypes, there are not useful markers for the diagnosis of BD. Therefore, diagnosis of BD is mostly based on symptoms. The patient in our study was negative for both HLA-B5 and HLA-B51. The patient in this report was born in the middle east and had GI, renal and mucocutaneous manifestations; oral and genital ulceration; eye inflammation; neurological involvement (dizziness, vertigo and neuropathy) and non-erosive, asymmetric, nondeforming arthritis. Many of these manifestations substantially subsided once the patient underwent the Upadacitinib or JAK 2 inhibitor therapy. In addition, the patient’s IC, GERD, intolerability toward many foods and maldigestion were also among symptoms that subsided with the immunomodulator. Furthermore, the patient’s thyroid and kidney functions all improved. And since she has been on Rinvoq, the patient’s left ear’s hearing loss no longer extend beyond the initial 30% (which occurred before the start of therapy). This brings up an important point about diagnosing patient with vestibular migraine, PPPD, fibromyalgia or anxiety without ruling out the presence of a rheumatological/ autoimmune disease. Another interesting future study would be to see the effect of immunomodulator therapy on patients suffering from endometriosis and IC.

Conclusion

Many Immunological/Rheumatoid diseases are manifested in multiple organs. It is essential to have a comprehensive assessment and investigation of possible autoimmune diseases as a cause of complex medical manifestations rather than focusing on one organ. Common diagnosis such as vestibular migraines, PPPD, bacterial overgrowth, fibromyalgia, and anxiey need better evaluation to rule out the possibility of autoimmune disease. In any suspected case of undifferentiated rheumatoid disease or overlapped syndrome, treatment with an immunomodulatory agent is preferred to bilological agents and can largely help the patient’s quality of life.

Acknowledgement

None.

Conflict of Interest

None.

References

1. De Stefano L, B. D'Onofrio, S. Gandolfo, E. Bozzalla Cassione and D. Mauro, et al. “Seronegative rheumatoid arthritis: One year in review 2023.” Clin Exp Rheumatol 41 (2023): 554-564.
2. Juliao-Banos, Fabian, Marcela Torres-Amaya, William Otero-Regino and Maria Teresa Vallejo, et al. "Guidelines for the management of ulcerative colitis in the adult population (update)." Colomb J Gastroenterol 35 (2020): 2-62.

   Google Scholar

3. Iacucci, Marietta, Shanika de Silva and Subrata Ghosh. "Mesalazine in inflammatory bowel disease: A trendy topic once again?." Can J Gastroenterol Hepatol 24 (2010): 127-133.

   Google Scholar, Crossref, Indexed at

4. Azarani, Arezou, Joelle Osias, Bulent Berker and Ceana Nezhat. "Endometriosis: Insights into its pathogenesis and treatment." Surg Technol Int 12 (2004): 178-181.

   Google Scholar, Indexed at

5. Hanno, Philip M., David Allen Burks, J. Quentin Clemens and Roger R. Dmochowski, et al. "AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome." Urol J 185 (2011): 2162-2170.

   Google Scholar, Crossref, Indexed at

6. Ilie, Mihaela Adriana, Constantin Caruntu, Mircea Tampa and Simona-Roxana Georgescu, et al. "Capsaicin: Physicochemical properties, cutaneous reactions and potential applications in painful and inflammatory conditions." Exp Ther Med 18 (2019): 916-925.

   Google Scholar, Crossref, Indexed at

7. Rossberger, Josefine, Magnus Fall and Ralph Peeker. "Critical appraisal of dimethyl sulfoxide treatment for interstitial cystitis discomfort, side-effects and treatment outcome." Scand J Urol Nephrol 39 (2005): 73-77.

   Google Scholar, Crossref, Indexed at

8. Generali, Joyce A. and Dennis J. Cada. "Intravesical heparin: Interstitial cystitis (painful bladder syndrome)." Hospital pharmacy 48 (2013): 822-824.

   Google Scholar, Crossref, Indexed at

9. Peck, Ammon B., Benjamin K. Canales and Cuong Q. Nguyen. "Oxalate-degrading microorganisms or oxalate-degrading enzymes: Which is the future therapy for enzymatic dissolution of calcium-oxalate uroliths in recurrent stone disease?" Urolithiasis 44 (2016): 45-50.

   Google Scholar, Crossref, Indexed at

10. Weidner, Till, Tanja Illing and Peter Elsner. "Primary localized cutaneous amyloidosis: A systematic treatment review." Am J Clin Dermatol 18 (2017): 629-642.

    Google Scholar, Crossref, Indexed at

11. Allen, Richard P. "Restless leg syndrome/Willis-Ekbom disease pathophysiology." Sleep Med Clin 10 (2015): 207-214.

    Google Scholar, Crossref, Indexed at

12. Staab, Jeffrey P. "Persistent postural-perceptual dizziness." Disorders of the vestibular system: Diagnosis and Manag (2023): 229-245.

    Google Scholar, Indexed at

13. Hansen, Pia S., Thomas H. Brix, Ivan Iachine and Kirsten O. Kyvik, et al. "The relative importance of genetic and environmental effects for the early stages of thyroid autoimmunity: A study of healthy Danish twins." Eur J Endocrinol 154 (2006): 29-38.

    Google Scholar, Crossref, Indexed at

14. Zhong, Jianyong, Hai-Chun Yang and Agnes B. Fogo. "A perspective on chronic kidney disease progression." Am J Physiol Renal Physiol 312 (2017): F375-F384.

    Google Scholar, Crossref, Indexed at

15. Devgire, Vikrant and Michael Hughes. "Raynaud's phenomenon." Br J Hosp Med 80 (2019): 658-664.

    Google Scholar

16. Clauw, Daniel J. "Fibromyalgia: A clinical review." Jama 311 (2014): 1547-1555.

    Google Scholar, Crossref, Indexed at

17. Zucchi, Dina, Elena Elefante, Emanuele Calabresi and Viola Signorini, et al. "One year in review 2019: Systemic lupus erythematosus." Clin Exp Rheumatol 37 (2019): 715-722.

    Google Scholar, Crossref, Indexed at

18. Duba, Ayyappa S. and Stephanie D. Mathew. "The seronegative spondyloarthropathies." Prim Care 45 (2018): 271-287.

    Google Scholar, Crossref, Indexed at

19. Greuter, Thomas and Stephan R. Vavricka. "Extraintestinal manifestations in inflammatory bowel disease–epidemiology, genetics and pathogenesis." Expert Rev Gastroenterol Hepatol 13 (2019): 307-317.

    Google Scholar, Crossref, Indexed at

20. Arvikar, Sheila L. and Mark C. Fisher. "Inflammatory bowel disease associated arthropathy." Curr Rev Musculoskelet 4 (2011): 123-131.

    Google Scholar, Crossref, Indexed at

21. Jacques, Peggy and Dirk Elewaut. "Joint expedition: Linking gut inflammation to arthritis." Mucosal Immunol 1 (2008): 364-371.

    Google Scholar, Crossref, Indexed at

22. Salmi, Marko and Sirpa Jalkanen. "Human leukocyte subpopulations from inflamed gut bind to joint vasculature using distinct sets of adhesion molecules." J Immunol 166 (2001): 4650-4657.

    Google Scholar, Crossref, Indexed at

23. Pepmueller, Peri Hickman. "Undifferentiated connective tissue disease, mixed connective tissue disease and overlap syndromes in rheumatology." Mo Med 113 (2016): 136.

    Google Scholar, Indexed at

24. Parente J, P. Mathurdas, L. Wandschneider and J. Aranha, et al. "Acta Med Port." Epub 24 (2011) 19-24.
25. Paul, S. and A. Keat. "Assessment of patients with spondyloarthropathies for treatment with tumour necrosis factor α blockade." Rheumatology 44 (2005): 17-23.

    Google Scholar, Crossref, Indexed at

26. Pugliese, Daniela, Carla Felice, Alfredo Papa and Antonio Gasbarrini, et al. "Anti TNF-α therapy for ulcerative colitis: Current status and prospects for the future." Expert Rev Clin Immunol 13 (2017): 223-233.

    Google Scholar, Crossref, Indexed at

27. Lu, XiaoQin, Rui Hu, Lin Peng and MengSi Liu, et al. "Efficacy and safety of adalimumab biosimilars: Current critical clinical data in rheumatoid arthritis." Front Immunol 12 (2021): 638444.

    Google Scholar, Crossref, Indexed at

28. Atiqi, S., M. Leeuw, F. Hooijberg and L. Boekel, et al. "Pos0659 long-term dynamics of antibody response to adalimumab detected with a drug tolerant assay." (2022): 601-602.

    Google Scholar

29. Kalden, Joachim R. and Hendrik Schulze-Koops. "Immunogenicity and loss of response to TNF inhibitors: Implications for rheumatoid arthritis treatment." Nat Rev Rheumatol 13 (2017): 707-718.

    Google Scholar, Crossref, Indexed at

30. Hu, Xiaoyi, Jing Li, Maorong Fu and Xia Zhao, et al. "The JAK/STAT signaling pathway: From bench to clinic." Signal Transduct Target Ther 6(1): 402.

    Google Scholar, Crossref, Indexed at

31. Banerjee, Shubhasree, Ann Biehl, Massimo Gadina and Sarfaraz Hasni, et al. "JAK–STAT signaling as a target for inflammatory and autoimmune diseases: Current and future prospects." Drugs 77 (2017): 521-546.

    Google Scholar, Crossref, Indexed at

32. Saadoun, David and Bertrand Wechsler. "Behçet's disease." Orphanet J Rare Dis 7 (2012): 1-6.

    Google Scholar, Indexed at

33. Bulur, Isil and Meltem Onder. "Behçet disease: New aspects." Clin Dermatol 35 (2017): 421-434.

    Google Scholar, Crossref, Indexed at

34. Kalra, Seema, Alan Silman, Gulsen Akman-Demir and Saeed Bohlega, et al. "Diagnosis and management of Neuro-Behçet’s disease: International consensus recommendations." J Neurol 261 (2014): 1662-1676.

    Google Scholar, Crossref, Indexed at